bluuebunny/crossref_metadata_2025 huggingface dataset:
Diabetic Macular Edema Detection Using End-to-End Deep Fusion Model and Anatomical Landmark Visualization on an Edge Computing Device
Authors: Wang Ting-Yuan , Chen Yi-Hao , Chen Jiann-Torng , Liu Jung-Tzu , Wu Po-Yi , Chang Sung-Yen , Lee Ya-Wen , Su Kuo-Chen , Chen Ching-Long
Published: April 2022

Purpose

Diabetic macular edema (DME) is a common cause of vision impairment and blindness in patients with diabetes. However, vision loss can be prevented by regular eye examinations during primary care. This study aimed to design an artificial intelligence (AI) system to facilitate ophthalmology referrals by physicians.

Methods

We developed an end-to-end deep fusion model for DME classification and hard exudate (HE) detection. Based on the architecture of fusion model, we also applied a dual model which included an independent classifier and object detector to perform these two tasks separately. We used 35,001 annotated fundus images from three hospitals between 2007 and 2018 in Taiwan to create a private dataset. The Private dataset, Messidor-1 and Messidor-2 were used to assess the performance of the fusion model for DME classification and HE detection. A second object detector was trained to identify anatomical landmarks (optic disc and macula). We integrated the fusion model and the anatomical landmark detector, and evaluated their performance on an edge device, a device with limited compute resources.

Results

For DME classification of our private testing dataset, Messidor-1 and Messidor-2, the area under the receiver operating characteristic curve (AUC) for the fusion model had values of 98.1, 95.2, and 95.8%, the sensitivities were 96.4, 88.7, and 87.4%, the specificities were 90.1, 90.2, and 90.2%, and the accuracies were 90.8, 90.0, and 89.9%, respectively. In addition, the AUC was not significantly different for the fusion and dual models for the three datasets (p = 0.743, 0.942, and 0.114, respectively). For HE detection, the fusion model achieved a sensitivity of 79.5%, a specificity of 87.7%, and an accuracy of 86.3% using our private testing dataset. The sensitivity of the fusion model was higher than that of the dual model (p = 0.048). For optic disc and macula detection, the second object detector achieved accuracies of 98.4% (optic disc) and 99.3% (macula). The fusion model and the anatomical landmark detector can be deployed on a portable edge device.

Conclusion

This portable AI system exhibited excellent performance for the classification of DME, and the visualization of HE and anatomical locations. It facilitates interpretability and can serve as a clinical reference for physicians. Clinically, this system could be applied to diabetic eye screening to improve the interpretation of fundus imaging in patients with DME.
Fecal Microbiota Transplantation Ameliorates Active Ulcerative Colitis by Downregulating Pro-inflammatory Cytokines in Mucosa and Serum
Authors: Zhang Wen-Hui , Jin Ze-Yu , Yang Zhong-Hua , Zhang Jia-Yi , Ma Xiao-Han , Guan Jing , Sun Bao-Lin , Chen Xi
Published: April 2022

Background

Ulcerative colitis (UC) is a multi-factor disease characterized by alternating remission periods and repeated occurrence. It has been shown that fecal microbiota transplantation (FMT) is an emerging and effective approach for UC treatment. Since most existing studies chose adults as donors for fecal microbiota, we conducted this study to determine the long-term efficacy and safety of the microbiota from young UC patient donors and illustrate its specific physiological effects.

Methods

Thirty active UC patients were enrolled and FMT were administered with the first colonoscopy and two subsequent enema/transendoscopic enteral tubing (TET) practical regimens in The First Affiliated Hospital of Anhui Medical University in China. Disease activity and inflammatory biomarkers were assessed 6 weeks/over 1 year after treatment. The occurrence of adverse events was also recorded. The samples from blood and mucosa were collected to detect the changes of inflammatory biomarkers and cytokines. The composition of gut and oral microbiota were also sampled and sequenced to confirm the alteration of microbial composition.

Results

Twenty-seven patients completed the treatment, among which 16 (59.3%) achieved efficacious clinical response and 11 (40.7%) clinical remission. Full Mayo score and calprotectin dropped significantly and remained stable over 1 year. FMT also significantly reduced the levels of C-reactive protein (CRP), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). The gut microbiota altered significantly with increased bacterial diversity and decreased metabolic diversity in responsive patients. The pro-inflammatory enterobacteria decreased after FMT and the abundance of Collinsella increased. Accordingly, the altered metabolic functions, including antigen synthesis, amino acids metabolism, short chain fatty acid production, and vitamin K synthesis of microbiota, were also corrected by FMT.

Conclusion

Fecal microbiota transplantation seems to be safe and effective for active UC patients who are nonresponsive to mesalazine or prednisone in the long-term. FMT could efficiently downregulate pro-inflammatory cytokines to ameliorate the inflammation.
Glutamate Metabotropic Receptor Type 3 (mGlu3) Localization in the Rat Prelimbic Medial Prefrontal Cortex
Authors: Woo Elizabeth , Datta Dibyadeep , Arnsten Amy F. T.
Published: April 2022

Metabotropic glutamate receptors type 3 (mGlu3, encoded by GRM3) are increasingly related to cognitive functioning, including the working memory operations of the prefrontal cortex (PFC). In rhesus monkeys, mGlu3 are most commonly expressed on glia (36%), but are also very prominent on layer III dendritic spines (23%) in the dorsolateral PFC (dlPFC) where they enhance working memory-related neuronal firing. In contrast, mGlu2 are predominately presynaptic in layer III of macaque dlPFC, indicating a pre- vs. post-synaptic dissociation by receptor subtype. The current study examined the cellular and subcellular localizations of mGlu3 in the rat prelimbic medial PFC (PL mPFC), a region needed for spatial working memory performance in rodents. Multiple label immunofluorescence demonstrated mGlu3 expression in neurons and astrocytes, with rare labeling in microglia. Immunoelectron microscopy of layers III and V found that the predominant location for mGlu3 was on axons (layer III: 35.9%; layer V: 44.1%), with labeling especially prominent within the intervaricose segments distant from axon terminals. mGlu3 were also found on glia (likely astrocytes), throughout the glial membrane (layer III: 28.2%; layer V: 29.5%). Importantly, mGlu3 could be seen on dendritic spines, especially in layer III (layer III: 15.6%; layer V: 8.2%), with minor labeling on dendrites. These data show that there are some similarities between mGlu3 expression in rat PL mPFC and macaque dlPFC, but the spine expression enriches and differentiates in the more recently evolved primate dlPFC.
Persistent Hiccups as an Atypical Presentation of SARS-CoV-2 Infection: A Systematic Review of Case Reports
Authors: Giannos Panagiotis , Katsikas Triantafyllidis Konstantinos , Geropoulos Georgios , Kechagias Konstantinos S.
Published: April 2022

Symptoms, such as fever, dry cough, dyspnoea, and respiratory distress, are commonly described in patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Recently, a growing number of cases pertained to persistent hiccups have been reported by SARS-CoV-2 infected patients. The aim of this systematic review was to screen the current literature and provide a summary of the reported cases of SARS-CoV-2 infected patients presenting with persistent hiccups. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, PubMed, Scopus, and Web of Science databases were searched from inception until October 2021. Case reports or case series that provided a separate clinical description for patients with presenting complaints of persistent hiccups before or after COVID-19 diagnosis were retrieved. The critical appraisal checklist for case reports provided by the Joanna Briggs Institute (JBI) was employed to evaluate the overall quality of the eligible studies. We identified 13 eligible studies that included 16 hospitalized COVID-19 patients who complained of persistent hiccups. The mean duration of hiccups was 4.6 days reported in 88% (14/16) patients. Hypertension was the most common comorbidity present in 50% (8/16) of patients followed by diabetes mellitus (4/16). Moreover, 44% (7/16) of patients received only one medication for managing the hiccups with metoclopramide (5/16) followed by chlorpromazine and baclofen (4/16) used as primary treatment. Equally, 44% of patients (7/16) received dexamethasone followed by azithromycin (5/16), ivermectin (4/16), and ceftriaxone (4/16) for managing the infection from SARS-CoV-2. The majority of patients (14/16) improved after initiation of treatment. Persistent hiccups are possibly a rare symptom that clinicians may expect to encounter in patients infected with SARS-CoV-2. Although there is not ample proof to propose causation, increased awareness about the diversity of presentations of SARS-CoV-2 infection could be crucial in the early recognition of the disease.
The Significance of Subclinical Epileptiform Activity in Alzheimer's Disease: A Review
Authors: Csernus Emoke Anna , Werber Tom , Kamondi Anita , Horvath Andras Attila
Published: April 2022

Hyperexcitability is a recently recognized contributor to the pathophysiology of Alzheimer's disease (AD). Subclinical epileptiform activity (SEA) is a neurophysiological sign of cortical hyperexcitability; however, the results of the studies in this field vary due to differences in the applied methodology. The aim of this review is to summarize the results of the related studies aiming to describe the characteristic features and significance of subclinical epileptiform discharges in the pathophysiologic process of AD from three different directions: (1) what SEA is; (2) why we should diagnose SEA, and (3) how we should diagnose SEA. We scrutinized both the completed and ongoing antiepileptic drug trials in AD where SEA served as a grouping variable or an outcome measure. SEA seems to appear predominantly in slow-wave sleep and in the left temporal region and to compromise cognitive functions. We clarify using supportive literature the high sensitivity of overnight electroencephalography (EEG) in the detection of epileptiform discharges. Finally, we present the most important research questions around SEA and provide an overview of the possible solutions.
Application of the Gait Deviation Index to Study Gait Impairment in Adult Population With Spinal Cord Injury: Comparison With the Walking Index for Spinal Cord Injury Levels
Authors: Sinovas-Alonso Isabel , Herrera-Valenzuela Diana , Cano-de-la-Cuerda Roberto , Reyes-Guzmán Ana de los , del-Ama Antonio J. , Gil-Agudo Ángel
Published: April 2022

The Gait Deviation Index (GDI) is a multivariate measure of overall gait pathology based on 15 gait features derived from three-dimensional (3D) kinematic data. GDI aims at providing a comprehensive, easy to interpret, and clinically meaningful metric of overall gait function. It has been used as an outcome measure to study gait in several conditions: cerebral palsy (CP), post-stroke hemiparetic gait, Duchenne muscular dystrophy, and Parkinson’s disease, among others. Nevertheless, its use in population with Spinal Cord Injury (SCI) has not been studied yet. The aim of the present study was to investigate the applicability of the GDI to SCI through the assessment of the relationship of the GDI with the Walking Index for Spinal Cord Injury (WISCI) II. 3D gait kinematics of 34 patients with incomplete SCI (iSCI) was obtained. Besides, 3D gait kinematics of a sample of 50 healthy volunteers (HV) was also gathered with Codamotion motion capture system. A total of 302 (iSCI) and 446 (HV) strides were collected. GDI was calculated for each stride and grouped for each WISCI II level. HV data were analyzed as an additional set. Normal distribution for each group was assessed with Kolmogorov-Smirnov tests. Afterward, ANOVA tests were performed between each pair of WISCI II levels to identify differences among groups (p < 0.05). The results showed that the GDI was normally distributed across all WISCI II levels in both iSCI and HV groups. Furthermore, our results showed an increasing relationship between the GDI values and WISCI II levels in subjects with iSCI, but only discriminative in WISCI II levels 13, 19, and 20. The index successfully distinguished HV group from all the individuals with iSCI. Findings of this study indicated that the GDI is not an appropriate multivariate walking metric to represent the deviation of gait pattern in adult population with iSCI from a normal gait profile when it is compared with the levels of walking impairment described by the WISCI II. Future work should aim at defining and validating an overall gait index derived from 3D kinematic gait variables appropriate for SCI, additionally taking into account other walking ability outcome measures.
A High Serum Phosphate and Calcium-Phosphate Product Is Associated With Cerebral Small Vascular Disease in Patients With Stroke: A Real-World Study
Authors: Lv Wenjing , Cui Can , Wang Zixuan , Jiang Junqi , Deng Binbin
Published: April 2022

Cerebral small vessel disease (CSVD) is a slowly progressive disease, often accompanied by stroke, and results in dementia, depression, and cognitive impairment. It was already known that calcium and phosphorus metabolism (CPM) disorders were associated with vascular-related adverse events. The risk factors of CSVD and the relationship between serum calcium (Ca), phosphorus (P), calcium-phosphate product (Ca × P), and CSVD in patients with stroke without CPM disorders are still obscure. In our study, 528 patients with stroke without CPM disorders were enrolled in a cohort from a consecutive hospital-based stroke registry, with 488 patients with CSVD as cases and 140 without CSVD as controls. The patients with CSVD were further sub-grouped into lacunes, white matter hyperintensities (WMHs), and cerebral microbleeds (CMBs). By applying univariate and multivariate logistic regression analysis, the following novel findings were obtained: (i) up to 76.19% of patients with stroke had signs of CSVD, and lacunes are the most common subtype. Notably, 22.96% of patients with CSVD had multiple subtypes coexisted. (ii) Compared with patients without CSVD, patients with CSVD had higher levels of age, rate of hypertension or diabetes, serum Ca, P, Ca × P, and lower levels of white blood cell (WBC) and hemoglobin (HB). (iii) We developed 2 predictive models and nomograms for predicting CSVD, in addition to the known factors (age and hypertension). The levels of P and Ca × P were positively correlated with the risk of CSVD (P: OR = 3,720.401, 95% CI (646.665–21,404.249); Ca × P: OR = 1.294, 95% CI (1.222–1.370)). (iv) The models were further validated in subtypes of CSVD, including lacunes, WMHs, and CMBs, and the results were still valid among the subtypes. In summary, CSVD was highly prevalent in patients with stroke, and high serum P and Ca × P are potential risk factors of CSVD and all subtypes including lacunes, WMHs, and CMBs.
Transformation Mechanism of Rare Ginsenosides in American Ginseng by Different Processing Methods and Antitumour Effects
Authors: Li Zhi-man , Shao Zi-jun , Qu Di , Huo Xiao-hui , Hua Mei , Chen Jian-bo , Lu Yu-shun , Sha Ji-Yue , Li Shan-shan , Sun Yin-shi
Published: April 2022

The mechanism by which ginsenosides from Panax quinquefolium L. transform into rare saponins by different processing methods and their antitumour effects have yet to be fully elucidated. Our study aimed to detect the effect of amino acids and processing methods on the conversion of ginsenosides in American ginseng to rare ginsenosides, using 8 monomeric ginsenosides as substrates to discuss the reaction pathway and mechanism. S180 tumour-bearing mice were established to study the antitumour effects of American ginseng total saponins (AGS-Q) or American ginseng total saponins after transformation (AGS-H) synergistic CTX. The results showed that aspartic acid was the best catalyst, and the thermal extraction method had the best effect. Under the optimal conditions, including a reaction temperature of 110°C, an aspartic acid concentration of 5%, a reaction time of 2.5 h and a liquid-solid ratio of 30 mL/g, the highest conversion of Rk1 and Rg5 was 6.58 ± 0.11 mg/g and 3.74 ± 0.05 mg/g, respectively. In the reaction pathway, the diol group saponins participated in the transformation process, and the triol group saponins basically did not participate in the transformation process. AGS-Q or AGS-H synergistic CTX, or AGS-H synergistic CTX/2 could significantly increase the tumour inhibition rate, spleen index and white blood cell count, had a significant upregulation effect on IL-2 and IL-10 immune cytokines; significantly restored the ratio of CD4+/CD8+; and significantly inhibited the level of CD4+CD25+. AGS-Q or AGS-H synergistic with CTX or CTX/2 can significantly upregulate the expression of Bax and cleaved-Caspase-3 and inhibit the expression of antiapoptotic protein Bcl-2. AGS synergistic CTX in the treatment of S180 tumour-bearing mice can improve the efficacy and reduce toxicity.
Association Between Dietary Total Antioxidant Capacity and Diet Quality in Adults
Authors: Salari-Moghaddam Asma , Nouri-Majd Saeedeh , Keshteli Ammar Hassanzadeh , Emami Fatemeh , Esmaillzadeh Ahmad , Adibi Peyman
Published: April 2022

Background

Diet quality is a major contributor to human health. In addition, antioxidants have a great contribution to several chronic conditions. The purpose of this study was to evaluate if dietary total antioxidant capacity (TAC) can be considered as a measure of diet quality in a Middle Eastern country.

Methods

In this cross-sectional study on 6,724 Iranian adults, we used a validated food frequency questionnaire (FFQ) to assess dietary intakes. Data derived from the FFQ was used to calculate dietary TAC and well-known diet quality scores including alternate healthy eating index (AHEI) and dietary diversity score (DDS). Dietary TAC was calculated based on the ferric reducing-antioxidant power (FRAP) values reported in earlier publications. AHEI and DDS have also been constructed based on previous publications. Cross-classification was used to examine the agreement between these measures.

Results

Mean age and BMI of study participants were 36.89 ± 8.08 y and 24.97 ± 3.87 kg/m2, respectively. We found that individuals in the highest tertile of dietary TAC had higher scores of AHEI (57.53 ± 0.20 vs. 52.03 ± 0.20, P < 0.001) and DDS (5.56 ± 0.03 vs. 4.15 ± 0.03, P < 0.001) compared with those in the lowest tertile. Participants' distribution on the basis of the cross-classification analysis indicated that the classifications were in exact agreement for 42.6%, within an adjacent tertile for 33.05%, and in gross misclassification for 20% of individuals. When this was examined between dietary TAC and DDS, we found that exact agreement in the classifications was for 59.2% of participants. Notably, a very low proportion of gross misclassification was seen in this regard such that only 6% of participants were classified in the opposing tertiles, indicating additional support for a good agreement.

Conclusion

We found that dietary TAC might be considered as a proper measure for the assessment of diet quality because it was well correlated with well-known measures of diet quality including DDS and AHEI scores.
Food-Approach Eating Behaviors and Brain Morphology: The Generation R Study
Authors: Dmitrichenko Olga , Mou Yuchan , Voortman Trudy , White Tonya , Jansen Pauline W.
Published: April 2022

Food-approach eating behaviors are associated with an increased risk of developing overweight/obesity and binge-eating disorder, while obesity and binge-eating disorder have also been linked with altered brain morphology in adults. To understand these associations, we examined the association of food-approach eating behaviors during childhood with adolescents' brain morphology. The sample included 1,781 adolescents with assessments of eating behaviors at ages 4 and 10 years and brain imaging data at 13 years from a large, population-based cohort. Food approach eating behaviors (enjoyment of food, emotional overeating, and food responsiveness) were assessed using the Child Eating Behavior Questionnaire. Additionally, we assessed binge eating symptoms using two items from the Development and Well-Being Assessment at 13 years of age. Adolescents participated in an MRI procedure and measures of brain morphology, including cerebral white, cerebral gray and subcortical gray matter volumes, were extracted from T1-weighted images processed using FreeSurfer. Enjoyment of food and food responsiveness at the age of 4 and 10 years were positively associated with cerebral white matter and subcortical gray matter volumes at age 13 years (e.g., enjoyment of food at 4 years and cerebral white matter: β = 2.73, 95% CI 0.51, 4.91). Enjoyment of food and food responsiveness at 4 years of age, but not at 10 years, were associated with a larger cerebral gray matter volume at 13 years of age (e.g., enjoyment of food at 4 years: β = 0.24, 95% CI 0.03, 0.45). No statistically significant associations were found for emotional overeating at both ages and brain measurements at 13 years of age. post-hoc analyses showed no associations of food-approach eating behaviors with amygdala or hippocampus. Lastly, we did not observe significant associations of binge-eating symptoms with global brain measurements and a priori-defined regions of interest, including the right frontal operculum, insular and orbitofrontal cortex. Our findings support an association between food-approach eating behaviors, especially enjoyment of food and food responsiveness, and brain morphology in adolescence. Our findings add important knowledge to previous studies that were mostly conducted in adults, by suggesting that the eating behavior-brain link may be visible earlier in life. Further research is needed to determine causality.
Knowledge and Preventive Practices About Osteoporosis Among Elementary School Teachers of Bandar-Abbas in 2020
Authors: Nikoobar Ali , Kolahi Ali-Asghar
Published: April 2022

Purpose

To assess knowledge and preventive practices about osteoporosis among elementary school teachers of Bandar-Abbas in 2020.

Materials and Methods

In this cross-sectional study, the schools were selected using simple random sampling, and the teachers were invited to fill out an online questionnaire. The knowledge section of the questionnaire assessed general knowledge and knowledge regarding risk/protective factors, nutrition, and physical activity. The preventive practices section assessed dietary habits using a food frequency questionnaire, asking about 16 items in six groups, intakes of which were compared to the recommendations of the Iranian food pyramid. This section also assessed physical activity using the International Physical Activity Questionnaire.

Results

Totally, 377 school teachers with a mean [standard deviation (SD)] age of 38 (6.7) participated in this study. The level of overall knowledge of 128 (33.9%) teachers was high, 222 (58.9%) moderate, and 27 (7.2%) low. The median [interquartile range (IQR)] intakes of fruits [2 (1–2)] and meats/eggs [1.7 (1.4–2.2)] were adequate, while those of dairy products [1.5 (0.9–2.3)], nuts/legumes [0.5 (0.2–1.1)], and vegetables [0.3 (0.1–1)] were inadequate. The median (IQR) intakes of tea/coffee [1 (0.6–2)] and cola [0.1 (0–0.3)] were considered limited. The physical activity level of 121 (32.1%) teachers was high, 124 (32.9%) moderate, and 135 (35%) low.

Conclusion

Knowledge of the teachers about osteoporosis was moderate, and their preventive practices were somewhat adequate concerning dietary habits and moderate concerning physical activity.
Comparison of Flavonoid Intake Assessment Methods Using USDA and Phenol Explorer Databases: Subcohort Diet, Cancer and Health-Next Generations—MAX Study
Authors: Lanuza Fabian , Bondonno Nicola P. , Zamora-Ros Raul , Rostgaard-Hansen Agnetha Linn , Tjønneland Anne , Landberg Rikard , Halkjær Jytte , Andres-Lacueva Cristina
Published: April 2022

Flavonoids are bioactive plant compounds that are widely present in the human diet. Estimating flavonoid intake with a high degree of certainty is challenging due to the inherent limitations of dietary questionnaires and food composition databases. This study aimed to evaluate the degree of reliability among flavonoid intakes estimated using four different approaches based on the two most comprehensive flavonoid databases, namely, United States Department of Agriculture (USDA) and Phenol Explorer (PE). In 678 individuals from the MAX study, a subcohort of the Diet, Cancer and Health-Next Generations cohort, dietary data were collected using three 24-h diet recalls over 1 year. Estimates of flavonoid intake were compared using flavonoid food content from PE as (1) aglycones (chromatography with hydrolysis), (2) aglycones transformed (converted from glycosides by chromatography without hydrolysis), (3) as they are in nature (glycosides, aglycones, and esters), and 4) using flavonoid content from USDA as aglycones (converted). Spearman's intra-class correlation (ICC) coefficient and weighted kappa (K) coefficient were calculated for the reliability analysis. When comparing PE total aglycones to USDA total aglycones, there was a moderate reliability when a continuous variable was used [ICC: 0.73, 95% confidence interval (CI): 0.70–0.76] and an excellent reliability when flavonoid intake was modeled as a categorical variable (K: 0.89, 95% CI: 0.88–0.90). The degree of reliability among all methods of estimated flavonoid intakes was very similar, especially between database pairs, for the flavanol subclass, while larger differences were observed for flavone, flavonol, and isoflavone subclasses. Our findings indicate that caution should be taken when comparing the results of the associations between flavonoid intakes and health outcomes from studies, when flavonoid intakes were estimated using different methods, particularly for some subclasses.
Extra-Oral Taste Receptors—Function, Disease, and Perspectives
Authors: Behrens Maik , Lang Tatjana
Published: April 2022

Taste perception is crucial for the critical evaluation of food constituents in human and other vertebrates. The five basic taste qualities salty, sour, sweet, umami (in humans mainly the taste of L-glutamic acid) and bitter provide important information on the energy content, the concentration of electrolytes and the presence of potentially harmful components in food items. Detection of the various taste stimuli is facilitated by specialized receptor proteins that are expressed in taste buds distributed on the tongue and the oral cavity. Whereas, salty and sour receptors represent ion channels, the receptors for sweet, umami and bitter belong to the G protein-coupled receptor superfamily. In particular, the G protein-coupled taste receptors have been located in a growing number of tissues outside the oral cavity, where they mediate important processes. This article will provide a brief introduction into the human taste perception, the corresponding receptive molecules and their signal transduction. Then, we will focus on taste receptors in the gastrointestinal tract, which participate in a variety of processes including the regulation of metabolic functions, hunger/satiety regulation as well as in digestion and pathogen defense reactions. These important non-gustatory functions suggest that complex selective forces have contributed to shape taste receptors during evolution.
Meta-Analysis of Shrinkage Mode After Neoadjuvant Chemotherapy for Breast Cancers: Association With Hormonal Receptor
Authors: Zheng Chun-Hui , Xu Kai , Shan Wen-Ping , Zhang Ya-Kun , Su Zhi-De , Gao Xiang-Jin , Wang Yu-Jue , Qi Jian-Yu , Ding Xiao-Yan , Wang Chun-Ping , Wang Yong-sheng
Published: April 2022

Background

Patients with concentric shrinkage mode after neoadjuvant chemotherapy (NAC) is considered to be ideal candidates for breast conserving treatment (BCT). While, what proportion of patients would represent CSM have not been well defined. This study was conducted to pool the rates of concentric shrinkage mode (CSM) in patients undergoing NAC, determine the impact of hormonal receptor on the shrinkage mode after NAC and estimate the rates of the CSM in various subgroups.

Methods

We conducted a systematic review following the guidelines for Meta-Analyses and Systematic reviews for the PRISMA guidelines. We systematically searched the literature about shrinkage mode after NAC from PubMed, Web of Science, Embase, The Cochrane Library, CNKI, Wanfang database published from January 2002 to June 2020 on breast cancer shrinkage mode after NAC and carefully screened the literature by using eligibility criteria: (1) patients with primary breast cancer treated with NAC; (2) publications with available data of shrinkage mode measured by magnetic resonance imaging (MRI), or data of pathology and hormonal receptor. The association between shrinkage mode and hormonal receptor was estimated using Stata 15.1 software.

Results

This analysis included a total of 2434 tumors from 23 papers. The included studies were heterogeneous (I2 = 89.4%, P<0.01). Random effects model was used to estimate the overall rates of CSM: 56.6% [95%CI (50.5%, 62.7%)]. According to the analysis of hormonal receptor, 10 of the paper was included for HR+ (hormone receptor positive) type analysis and the rate of CSM for HR+ type was 45.7% [95%CI (36.4%, 55.0%)]; 9 of the paper was used for HR- type (hormone receptor negative) analysis and the incidence of HR-CSM is 63.1% [95%CI (50.0%, 76.1%)]; with HR+ type as the control, the OR of the HR- CSM rate is 2.32 (1.32, 4.08) folds of HR+ type. From subgroup analyses, the CSM% of luminal A, luminal B, Her2+, and triple negative were 29.7% (16.5%, 42.8%); 47.2% (19.1%, 75.3%); 59.0% (39.7%, 78.3%); 66.2% (52.8%, 79.6%), respectively.

Conclusions

Breast cancer patients undergoing NAC did not get an ideal odds ratio of CSM. The incidence of CSM in breast cancer after NAC is associated with hormonal receptor. Patients with triple-negative breast cancers have the highest rates of CSM after NAC. More care should be taken to select patients with the luminal subtypes for BCT throughout NAC.
Bacteria−Based Synergistic Therapy in the Backdrop of Synthetic Biology
Authors: Bao Yawei , Cheng Yong , Liu Wei , Luo Wenguang , Zhou Peijie , Qian Dong
Published: April 2022

Although the synergistic effect of traditional therapies combined with tumor targeting or immunotherapy can significantly reduce mortality, cancer remains the leading cause of disease related death to date. Limited clinical response rate, drug resistance and off-target effects, to a large extent, impede the ceilings of clinical efficiency. To get out from the dilemmas mentioned, bacterial therapy with a history of more than 150 years regained great concern in recent years. The rise of biological engineering and chemical modification strategies are able to optimize tumor bacterial therapy in highest measure, and meanwhile avoid its inherent drawbacks toward clinical application such as bacteriotoxic effects, weak controllability, and low security. Here, we give an overview of recent studies with regard to bacteria-mediated therapies combined with chemotherapy, radiotherapy, and immunotherapy. And more than that, we review the bacterial detoxification and targeting strategies via biological reprogramming or chemical modification, their applications, and clinical transformation prospects.
Identification of a Hemizygous Novel Splicing Variant in ATRX Gene: A Case Report and Literature Review
Authors: Cong Yan , Wu Jie , Wang Hao , Wu Ke , Huang Cui , Yang Xuejian
Published: April 2022

Background

Alpha-thalassemia/intellectual disability syndrome (ATR-X) (OMIM # 301040) was first described by Wilkie et al. (1). Several studies found that children who presented with significantly consistent clinical phenotypes of hemoglobin H (Hb H) disease and profound mental handicap carried ATRX chromatin remodeler (ATRX, OMIM*300032) gene variants. With the recent development of exome sequencing (ES), ATRX gene variants of severe to profound intellectual disability without alpha-thalassemia have been implicated in intellectual disability-hypotonic facies syndrome, X-linked, 1(MRXHF1, OMIM #309580). These two diseases present similar clinical manifestations and the same pattern of inheritance.

Case Presentation

We reported a 3-year-old boy with intellectual disability, language impairment, hypotonia, and mild craniofacial abnormalities (flat nasal bridge, small and triangular nose, anteverted nostrils, and widely spaced incisors) and reviewed MRXHF1 cases. At an early stage, the patient developed global developmental delay (GDD). After 6 months of rehabilitation therapy, the patient's motor ability did not make big progress, as well as his speech or nonverbal communication. We performed whole-genome sequencing (WGS), Sanger sequencing, reverse transcription-polymerase chain reaction (RT-PCR), and X-inactivation studies. A novel hemizygous intronic variant in ATRX (c.5786+4A>G; NM_000489.6) was identified, which led to exon 24 skipping. The carrier mother showed extremely skewed X-chromosome inactivation (XCI). These results may contribute to the patient's phenotypes.

Conclusions

The novel hemizygous intronic variant in ATRX is the genetic etiology of the boy. Identification of this variant is helpful for parents to take prenatal diagnostic tests. Also, this new case expands the phenotypes of MRXHF1 and the mutational spectrum of the ATRX gene.
Kinase Inhibitors as Potential Therapeutic Agents in the Treatment of COVID-19
Authors: Naik Rajashri R. , Shakya Ashok K. , Aladwan Safwan M. , El-Tanani Mohamed
Published: April 2022

Corona virus is quickly spreading around the world. The goal of viral management is to disrupt the virus’s life cycle, minimize lung damage, and alleviate severe symptoms. Numerous strategies have been used, including repurposing existing antivirals or drugs used in previous viral outbreaks. One such strategy is to repurpose FDA-approved kinase inhibitors that are potential chemotherapeutic agents and have demonstrated antiviral activity against a variety of viruses, including MERS, SARS-CoV-1, and others, by inhibiting the viral life cycle and the inflammatory response associated with COVID-19. The purpose of this article is to identify licensed kinase inhibitors that have the ability to reduce the virus’s life cycle, from entrance through viral propagation from cell to cell. Several of these inhibitors, including imatinib, ruxolitinib, silmitasertib, and tofacitinib (alone and in conjunction with hydroxychloroquine), are now undergoing clinical studies to determine their efficacy as a possible treatment drug. The FDA approved baricitinib (a Janus kinase inhibitor) in combination with remdesivir for the treatment of COVID-19 patients receiving hospital care in November 2020. While in vitro trials with gilteritinib, fedratinib, and osimertinib are encouraging, further research is necessary before these inhibitors may be used to treat COVID-19 patients.
Sivelestat Alleviates Atherosclerosis by Improving Intestinal Barrier Function and Reducing Endotoxemia
Authors: Nie Hezhongrong , Xiong Qingquan , Lan Guanghui , Song Chunli , Yu Xiaohong , Chen Lei , Wang Daming , Ren Tingyu , Chen Zeyan , Liu Xintong , Zhou Yiwen
Published: April 2022

Emerging evidence suggests that atherosclerosis, one of the leading phenotypes of cardiovascular diseases, is a chronic inflammatory disease. During the atherosclerotic process, immune cells play critical roles in vascular inflammation and plaque formation. Meanwhile, gastrointestinal disorder is considered a risk factor in mediating the atherosclerotic process. The present study aimed to utilize sivelestat, a selective inhibitor of neutrophil elastase, to investigate its pharmacological benefits on atherosclerosis and disclose the gastrointestinal–vascular interaction. The activation of intestinal neutrophil was increased during atherosclerotic development in Western diet-fed ApoE-/- mice. Administration of sivelestat attenuated atherosclerotic phenotypes, including decreasing toxic lipid accumulation, vascular monocyte infiltration, and inflammatory cytokines. Sivelestat decreased intestinal permeability and endotoxemia in atherosclerotic mice. Mechanistically, sivelestat upregulated the expression of zonula occludens-1 in the atherosclerotic mice and recombinant neutrophil elastase protein-treated intestinal epithelial cells. Meanwhile, treatment of sivelestat suppressed the intestinal expression of inflammatory cytokines and NF-κB activity. In contrast, administration of lipopolysaccharides abolished the anti-atherosclerotic benefits of sivelestat in the Western diet-fed ApoE-/- mice. Further clinical correlation study showed that the circulating endotoxin level and intestinal neutrophil elastase activity were positively correlated with carotid intima-medial thickness in recruited subjects. In conclusion, sivelestat had pharmacological applications in protection against atherosclerosis, and intestinal homeostasis played one of the critical roles in atherosclerotic development.
Atrazine and Diuron Effects on Survival, Embryo Development, and Behavior in Larvae and Adult Zebrafish
Authors: Zaluski Amanda B. , Wiprich Melissa T. , de Almeida Luiza F. , de Azevedo Andressa P. , Bonan Carla D. , Vianna Monica R. M.
Published: April 2022

Atrazine and Diuron are widely used herbicides. The use of pesticides contaminates the aquatic environment, threatening biodiversity and non-target organisms such as fish. In this study, we investigated the effects of acute exposure for 96 h hours to atrazine and diuron commercial formulations in zebrafish (Danio rerio, wild-type AB) embryos and larvae and adult stages. We observed a significant concentration-dependent survival decrease and hatching delays in animals exposed to both herbicides and in the frequency of malformations compared to the control groups. Morphological defects included cardiac edema, tail reduction, and head malformation. At 7 days post-fertilization (dpf), atrazine exposure resulted in a reduction in the head length at 2, 2.5, and 5 mg/L and increased the ocular distance at 1, 2, 2.5, and 5 mg/L atrazine when compared to controls. At the same age, diuron increased the ocular distance in animals exposed to diuron (1.0 and 1.5 mg/L) and no effects were observed on the head length. We also evaluated a behavioral repertoire in larvae at 7 dpf, and there were no significant differences in distance traveled, mean speed, time in movement, and thigmotaxis for atrazine and diuron when animals were individually placed in a new environment. The cognitive ability of the larvae was tested at 7 dpf for avoidance and optomotor responses, and neither atrazine nor diuron had significant impacts when treated groups were compared to their corresponding controls. Adults’ behavior was evaluated 7 and 8 days after the end of the acute herbicide exposure. Exploration of a new environment and associated anxiety-like parameters, social interaction, and aggressiveness were not altered. Our results highlight the need for further studies on the sublethal effects of both herbicides and the consideration of the effects of commercial formulas vs. isolated active ingredients. It also emphasizes the need to take sublethal effects into consideration when establishing the environmental limits of residues.
Continuity and Completeness of Electronic Health Record Data for Patients Treated With Oral Hypoglycemic Agents: Findings From Healthcare Delivery Systems in Taiwan
Authors: Hsu Chien-Ning , Huang Kelly , Lin Fang-Ju , Ou Huang-Tz , Huang Ling-Ya , Kuo Hsiao-Ching , Wang Chi-Chuan , Toh Sengwee
Published: April 2022

Objective: To evaluate the continuity and completeness of electronic health record (EHR) data, and the concordance of select clinical outcomes and baseline comorbidities between EHR and linked claims data, from three healthcare delivery systems in Taiwan.

Methods: We identified oral hypoglycemic agent (OHA) users from the Integrated Medical Database of National Taiwan University Hospital (NTUH-iMD), which was linked to the National Health Insurance Research Database (NHIRD), from June 2011 to December 2016. A secondary evaluation involved two additional EHR databases. We created consecutive 90-day periods before and after the first recorded OHA prescription and defined patients as having continuous EHR data if there was at least one encounter or prescription in a 90-day interval. EHR data completeness was measured by dividing the number of encounters in the NTUH-iMD by the number of encounters in the NHIRD. We assessed the concordance between EHR and claims data on three clinical outcomes (cardiovascular events, nephropathy-related events, and heart failure admission). We used individual comorbidities that comprised the Charlson comorbidity index to examine the concordance of select baseline comorbidities between EHRs and claims.

Results: We identified 39,268 OHA users in the NTUH-iMD. Thirty-one percent (n = 12,296) of these users contributed to the analysis that examined data continuity during the 6-month baseline and 24-month follow-up period; 31% (n = 3,845) of the 12,296 users had continuous data during this 30-month period and EHR data completeness was 52%. The concordance of major cardiovascular events, nephropathy-related events, and heart failure admission was moderate, with the NTU-iMD capturing 49–55% of the outcome events recorded in the NHIRD. The concordance of comorbidities was considerably different between the NTUH-iMD and NHIRD, with an absolute standardized difference >0.1 for most comorbidities examined. Across the three EHR databases studied, 29–55% of the OHA users had continuous records during the 6-month baseline and 24-month follow-up period.

Conclusion: EHR data continuity and data completeness may be suboptimal. A thorough evaluation of data continuity and completeness is recommended before conducting clinical and translational research using EHR data in Taiwan.
A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities
Authors: Zhang Miao-Qing , Zhang Jing-Pu , Hu Chang-Qin
Published: April 2022

Impurities in pharmaceuticals of potentially hazardous materials may cause drug safety problems. Macrolide antibiotic preparations include active pharmaceutical ingredients (APIs) and different types of impurities with similar structures, and the amount of these impurities is usually very low and difficult to be separated for toxicity evaluation. Our previous study indicated that hepatotoxicity induced by macrolides was correlated with c-fos overexpression. Here, we report an assessment of macrolide-related liver toxicity by ADMET prediction, molecular docking, structure–toxicity relationship, and experimental verification via detection of the c-fos gene expression in liver cells. The results showed that a rapid assessment model for the prediction of hepatotoxicity of macrolide antibiotics could be established by calculation of the -CDOCKER interaction energy score with the FosB/JunD bZIP domain and then confirmed by the detection of the c-fos gene expression in L02 cells. Telithromycin, a positive compound of liver toxicity, was used to verify the correctness of the model through comparative analysis of liver toxicity in zebrafish and cytotoxicity in L02 cells exposed to telithromycin and azithromycin. The prediction interval (48.1∼53.1) for quantitative hepatotoxicity in the model was calculated from the docking scores of seven macrolide antibiotics commonly used in clinics. We performed the prediction interval to virtual screening of azithromycin impurities with high hepatotoxicity and then experimentally confirmed by liver toxicity in zebrafish and c-fos gene expression. Simultaneously, we found the hepatotoxicity of azithromycin impurities may be related to the charge of nitrogen (N) atoms on the side chain group at the C5 position via structure–toxicity relationship of azithromycin impurities with different structures. This study provides a theoretical basis for improvement of the quality of macrolide antibiotics.
Maresin1 Protect Against Ferroptosis-Induced Liver Injury Through ROS Inhibition and Nrf2/HO-1/GPX4 Activation
Authors: Yang Wenchang , Wang Yaxin , Zhang Chenggang , Huang Yongzhou , Yu Jiaxian , Shi Liang , Zhang Peng , Yin Yuping , Li Ruidong , Tao Kaixiong
Published: April 2022

Drugs, viruses, and chemical poisons stimulating live in a short period of time can cause acute liver injury (ALI). ALI can further develop into serious liver diseases such as cirrhosis and liver cancer. Therefore, how to effectively prevent and treat ALI has become the focus of research. Numerous studies have reported Maresin1 (MaR1) has anti-inflammatory effect and protective functions on organs. In the present study, we used d-galactosamine/lipopolysaccharide (D-GalN/LPS) to establish an ALI model, explored the mechanism of liver cells death caused by D-GalN/LPS, and determined the effect of MaR1 on D-GalN/LPS-induced ALI. In vivo experiments, we found that MaR1 and ferrostatin-1 significantly alleviated D-GalN/LPS-induced ALI, reduced serum alanine transaminase and aspartate transaminase levels, and improved the survival rate of mice. Meanwhile, MaR1 inhibited hepatocyte death, inhibited tissue reactive oxygen species (ROS) expression, reduced malondialdehyde (MDA), reduced glutathione (GSH), GSH/oxidized glutathione (GSSG), and iron content induced by D-GalN/LPS in mice. In addition, MaR1 inhibited ferroptosis-induced liver injury through inhibiting the release of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6. Subsequently, western blot showed that MaR1 improved the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4). In vitro experiments, we found that MaR1 inhibited LPS-induced and erastin-induced cell viability reduction. Meanwhile, we found that MaR1 increased the MDA and GSH levels in cells. Western blot showed that MaR1 increased the expression level of Nrf2/HO-1/GPX4. Next, the Nrf2 was knocked down in HepG2 cells, and the results showed that the protective effect of MaR1 significantly decreased. Finally, flow cytometry revealed that MaR1 inhibited ROS production and apoptosis. Overall, our study showed MaR1 inhibited ferroptosis-induced liver injury by inhibiting ROS production and Nrf2/HO-1/GPX4 activation.
Ethnic Diversity and Warfarin Pharmacogenomics
Authors: Asiimwe Innocent G. , Pirmohamed Munir
Published: April 2022

Warfarin has remained the most commonly prescribed vitamin K oral anticoagulant worldwide since its approval in 1954. Dosing challenges including having a narrow therapeutic window and a wide interpatient variability in dosing requirements have contributed to making it the most studied drug in terms of genotype-phenotype relationships. However, most of these studies have been conducted in Whites or Asians which means the current pharmacogenomics evidence-base does not reflect ethnic diversity. Due to differences in minor allele frequencies of key genetic variants, studies conducted in Whites/Asians may not be applicable to underrepresented populations such as Blacks, Hispanics/Latinos, American Indians/Alaska Natives and Native Hawaiians/other Pacific Islanders. This may exacerbate health inequalities when Whites/Asians have better anticoagulation profiles due to the existence of validated pharmacogenomic dosing algorithms which fail to perform similarly in the underrepresented populations. To examine the extent to which individual races/ethnicities are represented in the existing body of pharmacogenomic evidence, we review evidence pertaining to published pharmacogenomic dosing algorithms, including clinical utility studies, cost-effectiveness studies and clinical implementation guidelines that have been published in the warfarin field.