bluuebunny/crossref_metadata_2025 huggingface dataset:
A Minimalist Model of Salt-Marsh Vegetation Dynamics Driven by Species Competition and Dispersal
Authors: Finotello Alvise , D’Alpaos Andrea , Marani Marco , Bertuzzo Enrico
Published: April 2022

We present a new bidimensional, spatially-explicit ecological model describing the dynamics of halophytic vegetation in tidal saline wetlands. Existing vegetation models employ relatively simple deterministic or stochastic mechanisms, and are driven by local environmental conditions. In the proposed model, in contrast, vegetation dynamics depend not only on the marsh local habitat, but also on spatially-explicit mechanisms of dispersal and competition among multiple interacting species. The role of habitat quality, here determined by the local elevation relative to the mean sea level as a proxy for environmental conditions, is mathematically modeled by a logistic function that represents the fundamental (theoretical) niche of each halophytic species. Hence, the model does not artificially impose any constraints to the ability of a species to colonize elevated areas where it is usually not observed: such limitations naturally arise through competition with fitter species across marsh topographic gradients. We qualitatively test our model against field data based on a suitable assemblage of focus species, and perform a sensitivity analysis aimed at determining how dynamic equilibria in vegetation distributions are affected by changes in model input parameters. Results indicate that the model is robust and can predict realistic vegetation distributions and species-richness patterns. More importantly, the model is also able to effectively reproduce the outcomes of classical ecological experiments, wherein a species is transplanted to an area outside its realized niche. A direct comparison shows that previous models not accounting for dispersal and interspecific competitions are unable to reproduce such dynamics. Our model can be easily integrated into virtually any existing morphodynamic model, thereby strengthening our ability to simulate the coupled biotic and abiotic evolution of salt marshes under changing climate forcings.
Drivers of Biomass and Biodiversity of Non-Chemosynthetic Benthic Fauna of the Mid-Atlantic Ridge in the North Atlantic
Authors: Priede Imants G. , Muller-Karger Frank E. , Niedzielski Tomasz , Gebruk Andrey V. , Jones Daniel O. B. , Colaço Ana
Published: April 2022

We examine the main drivers that may elevate biomass and biodiversity of non-chemosynthetic benthic megafauna of the lower bathyal (800-3500m depth) of the Mid-Atlantic Ridge in the North Atlantic Ocean (MAR). Specifically: 1. Primary production in surface waters (10°-48°N) from remote sensing data 2002-2020 over the MAR was not significantly different from abyssal regions to the east and west. We reject the hypothesis that presence of a mid ocean ridge may enhance surface primary production. 2. The quantity of particulate organic matter reaching the sea floor was estimated as a proportion of surface export production scaled by bathymetry. Flux was 1.3 to 3.0 times greater on the MAR as a function of shorter vertical transport distance from the surface than on adjacent abyssal regions. 3. Depth variation effect on species richness. Demersal fishes living between 41° and 60°N showed a maximum of species richness at 2000 m depth and linear increase in regional (Gamma) diversity of 32 species per 1,000 m elevation of the MAR above the abyss. Elevated topography provides niches for species that cannot otherwise survive. 4. Substrate heterogeneity. The MAR >95% covered with soft sediment with frequent hard rocky patches spaced at a mean nearest neighbour distance of <500 m. Over 90% were <1 km apart. Animals are readily able to disperse between such patches increasing biodiversity through the additive effect of soft and hard substrate fauna on the MAR. 5. Presence of a biogeographic overlap zone. The MAR harbours bathyal species known from Western Atlantic and Eastern Atlantic continental slopes with meridional asymmetry resulting in bias toward predominance of Eastern species. The mix of species contributes to increased diversity to the east of the MAR. Multiple factors support increase in biomass and biodiversity on the MAR. Biological data are almost entirely absent from 12° to 33°N, the part of the MAR which may be mined for polymetallic sulphide ore deposits. This study enables some predictions of biomass and biodiversity but there is urgent need for intensive biological sampling across the MAR throughout the proposed mining areas south of the Azores.
Characteristics and Comparison of Adverse Events of Coronavirus Disease 2019 Vaccines Reported to the United States Vaccine Adverse Event Reporting System Between 14 December 2020 and 8 October 2021
Authors: Zou Chenyu , Xue Xiangzhong , Qian Jingjing
Published: April 2022

Background

This study assessed and compared the frequency and type of adverse events (AEs) of the Pfizer-BioNTech, Moderna, and Janssen coronavirus disease 2019 (COVID-19) vaccines reported in the Vaccine Adverse Event Reporting System (VAERS).

Methods

A retrospective analysis examined VAERS reports between 14 December 2020 and 8 October 2021 and focused on AE reports related to COVID-19 vaccines and AE outcomes [e.g., emergency room (ER) visits after being vaccinated, hospitalization, prolongation of existing hospitalization, life-threatening events, disability, birth defect, and death]. Reporting odds ratios (RORs) and Breslow-Day statistics were used to compare AE reporting between COVID-19 and non-COVID vaccines and between individual COVID-19 vaccines.

Results

A total of 604,157 AEs of COVID-19 vaccines were reported, including 43.51% for the Pfizer-BioNTech vaccine, 47.13% for the Moderna vaccine, and 9.12% for the Janssen COVID-19 vaccine. About 12.56% of patients visited ER after being vaccinated, 5.96% reported hospitalization, and 1.52% reported life-threatening events. Among the number of death cases (n = 7,674; mean age = 73), 2,025 patients (26.39%) had hypertension and 1,237 (16.12%) patients had cancer. RORs between COVID-19 vaccines and non-COVID vaccines identified increased ROR in ER visits, hospitalization, and life-threatening events. The results of the Breslow-Day statistics indicated heterogeneities between the disproportionality of reports across the four serious AE outcomes (i.e., ER visits, hospitalization, life-threatening events, and disability) between individual COVID-19 vaccines.

Conclusion

Most current VAERS reports showed that the most commonly reported AEs of COVID-19 vaccines were mild. Cases with a mortality outcome tended to occur in older adults with underneath conditions. Close ongoing surveillance in the safety of COVID-19 vaccines is critical and will inform the use of individual COVID-19 vaccines. Given the known limitations associated with the passive spontaneous reporting system, such as VAERS, our findings need to be further assessed and verified through longitudinal, large healthcare data systems.
In silico Effects of Synaptic Connections in the Visual Thalamocortical Pathway
Authors: Sasi Swapna , Sen Bhattacharya Basabdatta
Published: April 2022

We have studied brain connectivity using a biologically inspired in silico model of the visual pathway consisting of the lateral geniculate nucleus (LGN) of the thalamus, and layers 4 and 6 of the primary visual cortex. The connectivity parameters in the model are informed by the existing anatomical parameters from mammals and rodents. In the base state, the LGN and layer 6 populations in the model oscillate with dominant alpha frequency, while the layer 4 oscillates in the theta band. By changing intra-cortical hyperparameters, specifically inhibition from layer 6 to layer 4, we demonstrate a transition to alpha mode for all the populations. Furthermore, by increasing the feedforward connectivities in the thalamo-cortico-thalamic loop, we could transition into the beta band for all the populations. On looking closely, we observed that the origin of this beta band is in the layer 6 (infragranular layers); lesioning the thalamic feedback from layer 6 removed the beta from the LGN and the layer 4. This agrees with existing physiological studies where it is shown that beta rhythm is generated in the infragranular layers. Lastly, we present a case study to demonstrate a neurological condition in the model. By changing connectivities in the network, we could simulate the condition of significant (P < 0.001) decrease in beta band power and a simultaneous increase in the theta band power, similar to that observed in Schizophrenia patients. Overall, we have shown that the connectivity changes in a simple visual thalamocortical in silico model can simulate state changes in the brain corresponding to both health and disease conditions.
Age-Related Inflammation and Oxidative Stress in the Cochlea Are Exacerbated by Long-Term, Short-Duration Noise Stimulation
Authors: Fuentes-Santamaría Verónica , Alvarado Juan Carlos , Mellado Susana , Melgar-Rojas Pedro , Gabaldón-Ull María Cruz , Cabanes-Sanchis José J. , Juiz José M.
Published: April 2022

We have previously reported that young adult rats exposed to daily, short-duration noise for extended time periods, develop accelerated presbycusis starting at 6 months of age. Auditory aging is associated with progressive hearing loss, cell deterioration, dysregulation of the antioxidant defense system, and chronic inflammation, among others. To further characterize cellular and molecular mechanisms at the crossroads between noise and age-related hearing loss (ARHL), 3-month-old rats were exposed to a noise-accelerated presbycusis (NAP) protocol and tested at 6 and 16 months of age, using auditory brainstem responses, Real-Time Reverse Transcription-Quantitative PCR (RT-qPCR) and immunocytochemistry. Chronic noise-exposure leading to permanent auditory threshold shifts in 6-month-old rats, resulted in impaired sodium/potassium activity, degenerative changes in the lateral wall and spiral ganglion, increased lipid peroxidation, and sustained cochlear inflammation with advancing age. Additionally, at 6 months, noise-exposed rats showed significant increases in the gene expression of antioxidant enzymes (superoxide dismutase 1/2, glutathione peroxidase 1, and catalase) and inflammation-associated molecules [ionized calcium binding adaptor molecule 1, interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha]. The levels of IL-1β were upregulated in the spiral ganglion and spiral ligament, particularly in type IV fibrocytes; these cells showed decreased levels of connective tissue growth factor and increased levels of 4-hydroxynonenal. These data provide functional, structural and molecular evidence that age-noise interaction contributes to exacerbating presbycusis in young rats by leading to progressive dysfunction and early degeneration of cochlear cells and structures. These findings contribute to a better understanding of NAP etiopathogenesis, which is essential as it affects the life quality of young adults worldwide.
Perspectives on Understanding Aberrant Brain Networks in Epilepsy
Authors: Sinha Nishant , Joshi Rasesh B. , Sandhu Mani Ratnesh S. , Netoff Theoden I. , Zaveri Hitten P. , Lehnertz Klaus
Published: April 2022

Epilepsy is a neurological disorder affecting approximately 70 million people worldwide. It is characterized by seizures that are complex aberrant dynamical events typically treated with drugs and surgery. Unfortunately, not all patients become seizure-free, and there is an opportunity for novel approaches to treat epilepsy using a network view of the brain. The traditional seizure focus theory presumed that seizures originated within a discrete cortical area with subsequent recruitment of adjacent cortices with seizure progression. However, a more recent view challenges this concept, suggesting that epilepsy is a network disease, and both focal and generalized seizures arise from aberrant activity in a distributed network. Changes in the anatomical configuration or widespread neural activities spanning lobes and hemispheres could make the brain more susceptible to seizures. In this perspective paper, we summarize the current state of knowledge, address several important challenges that could further improve our understanding of the human brain in epilepsy, and invite novel studies addressing these challenges.
Structural and Functional Alterations of Substantia Nigra and Associations With Anxiety and Depressive Symptoms Following Traumatic Brain Injury
Authors: Gao Liang , Xue Qiang , Gong Shun , Li Gaoyi , Tong Wusong , Fan Mingxia , Chen Xianzhen , Yin Jia , Song Yu , Chen Songyu , Huang Jingrong , Wang Chengbin , Dong Yan
Published: April 2022

Backgrounds

Although there are a certain number of studies dedicated to the disturbances of the dopaminergic system induced by traumatic brain injury (TBI), the associations of abnormal dopaminergic systems with post-traumatic anxiety and depressive disorders and their underlying mechanisms have not been clarified yet. In the midbrain, dopaminergic neurons are mainly situated in the substantia nigra (SN) and the ventral tegmental area (VTA). Thus, we selected SN and VTA as regions of interest and performed a seed-based global correlation to evaluate the altered functional connectivity throughout the dopaminergic system post-TBI.

Methods

Thirty-three individuals with TBI and 21 healthy controls were recruited in the study. Anxiety and depressive symptoms were examined by the Hospital Anxiety and Depression Scale. All MRI data were collected using a Siemens Prisma 3.0 Tesla MRI system. The volume of SN and the global functional connectivity of the SN and VTA were analyzed.

Results

In the present study, patients with TBI reported more anxiety and depressive symptoms. More importantly, some structural and functional alterations, such as smaller SN and reduced functional connectivity in the left SN, were seen in individuals with TBI. Patients with TBI had smaller substantia nigra on both right and left sides, and the left substantia nigra was relatively small in contrast with the right one. Among these findings, functional connectivity between left SN and left angular gyrus was positively associated with post-traumatic anxiety symptoms and negatively associated with depressive symptoms.

Conclusions

The TBI causes leftward lateralization of structural and functional alterations in the substantia nigra. An impaired mesocortical functional connectivity might be implicated in post-traumatic anxiety and depression.
Applications in Awake Animal Magnetic Resonance Imaging
Authors: Ferris Craig F.
Published: April 2022

There are numerous publications on methods and applications for awake functional MRI across different species, e.g., voles, rabbits, cats, dogs, and rhesus macaques. Each of these species, most obviously rhesus monkey, have general or unique attributes that provide a better understanding of the human condition. However, much of the work today is done on rodents. The growing number of small bore (≤30 cm) high field systems 7T- 11.7T favor the use of small animals. To that point, this review is primarily focused on rodents and their many applications in awake function MRI. Applications include, pharmacological MRI, drugs of abuse, sensory evoked stimuli, brain disorders, pain, social behavior, and fear.
Integrative Analysis of Pharmacokinetic and Metabolomic Profiles for Predicting Metabolic Phenotype and Drug Exposure Caused by Sotorasib in Rats
Authors: Du Ping , Liu Lihong , Hu Ting , An Zhuoling
Published: April 2022

Sotorasib is a novel targeted inhibitor of Kirsten rat sarcoma (KRAS) (G12C) that has shown exciting tumor-suppressing effects not only for single targeted agents but also for combination with immune checkpoint inhibitors. However, no integrative analysis of the pharmacokinetics (PK) and pharmacometabolomics (PM) of sotorasib has been reported to date. In the present study, a sensitive and robust high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method was firstly developed and fully validated for the quantitation of sotorasib in rat plasma. After one-step protein precipitation, sotorasib and an internal standard (carbamazepine) were separated on a Waters XBrige C18 column (50 mm × 2.1 mm, 3.5 μm) and analyzed in electrospray ionization positive ion (ESI+) mode. The optimized method was fully validated according to guidance and was successfully applied for the PK study of sotorasib at a dose of 10 mg/kg. In addition, a longitudinal and transversal PM was employed and correlated with PK using partial least squares model and Pearson’s analysis. With multivariate statistical analysis, the selected six (AUC model) and nine (Cmax model) metabolites completely distinguished the high- and low-exposure groups after sotorasib treatment, which indicates that these potential biomarkers can predict drug exposure or toxicity. The results of this study will not only shed light on how sotorasib disturbs the metabolic profiles and the relationship between PK and PM but also offer meaningful references for precision therapy in patients with the KRAS (G12C) mutation.
The Development and Validation of a Nomogram Incorporating Clinical, Pathological, and Therapeutic Features to Predict Overall Survival in Patients With Penile Cancer: A SEER-Based Study
Authors: Li Ruidan , Cheng Ke , Wei Zhigong , Liu Zheran , Peng Xingchen
Published: April 2022

Objective

This study aimed to investigate the prognostic factors of penile cancer and establish a comprehensive predictive model for clinical application.

Methods

A total of 581 patients from the Surveillance, Epidemiology, and End Results (SEER) program (2000–2018) were used to develop the prognostic model. The multivariate Cox proportional hazards regression was performed to identify independent prognostic factors to develop the nomogram. The performance of this model was validated internally by a cohort with 143 patients from the SEER database and validated externally by a cohort with 70 patients from the West China Hospital, Sichuan University (2010–2020).

Results

Age, marital status, size of the primary lesion, primary tumor (T), regional lymph nodes status, distant metastasis (M), and the surgery of regional lymph node (LND) were the independent prognostic factors for overall survival (OS) and were incorporated in the prognostic model. The prognostic nomogram showed a good risk stratification ability for OS in the development cohort, internal validation cohort, and external validation cohort.

Conclusion

This study incorporates the clinical, pathological, and therapeutic features comprehensively to develop a novel and clinically effective prognostic model for patients with penile cancer.
Ozone Exposure and Asthma Attack in Children
Authors: Huang Wanting , Wu Jinzhun , Lin Xiaoliang
Published: April 2022

Background

Increasing evidence indicated that ozone (O3) exposure could trigger asthma attacks in children. However, the effect of O3 at low concentrations is uncertain.

Purpose

This study aimed to explore the effects of O3 exposure at low concentrations on asthma attacks in children.

Methods

A total of 3,475 children with asthma attacks from the First Affiliated Hospital of Xiamen University were available for the analyses. Air pollution data and meteorological data in Xiamen during 2016–2019 were also collected. A case-crossover design and conditional logistic regression models were conducted to evaluate the association between asthma attacks and outdoor air pollution with lag structures (from lag 0 to lag 6) in both single and multi-pollutant models. Furthermore, we estimated the influence of various levels of O3 exposure on an asthma attack in three groups categorized by maximum daily 8-h sliding average ozone (O3-8 h) (O3-8 h ≥ 100 μg/m3, O3-8 h: 80–99 μg/m3, O3-8 h < 80 μg/m3).

Results

For both single-pollutant models and multi-pollutant models, when O3-8 h was higher than 80 μg/m3, O3 exposure was increased the risk of acute asthma attacks on each day of lag. The effect of O3 on children with asthma was significant when O3 concentration was higher than 100 μg/m3.

Conclusion

O3 concentration above 80 μg/m3 contributed to an increased risk of asthma attacks in children.
Structural Inequities and Barriers to Accessing Kidney Healthcare Services in the United States: A Focus on Uninsured and Undocumented Children and Young Adults
Authors: Iorember Franca M. , Bamgbola Oluwatoyin F.
Published: April 2022

The population of children living in poverty and lacking healthcare insurance has increased in the United States of America in the last decade. Several factors have been responsible for this trend including illegal immigration, socioeconomic deprivation, young age, racial segregation, environmental degradation, and discriminatory housing policies. These systemic barriers have contributed to the exclusion of families from essential healthcare services. They are also contributory to the development of chronic illnesses (such as dialysis-dependent kidney disease) that are debilitating and frequently require considerable therapeutic resources. This unfortunate scenario creates a never-ending vicious cycle of poverty and diseases in a segment of society. For pediatric nephrologists, the challenges of caring for uninsured children with chronic kidney disease are all too familiar. Federally funded healthcare programs do not cover this patient population, leaving them the option of seeking care in emergency healthcare settings. Presentation with a critical illness often necessitates urgent placement of vascular catheters and the choice of acute hemodialysis. Adverse social environment influences the need for protracted chronic hemodialysis and a delay in kidney transplantation. Consequently, there is greater comorbidity, recurrent hospitalization, and a higher mortality rate. New policies should address the deficit in health insurance coverage while promoting social programs that will remove structural barriers to health care resources for undocumented children and young adults.
Efficacy and Outcome of Remdesivir and Tocilizumab Combination Against Dexamethasone for the Treatment of Severe COVID-19: A Randomized Controlled Trial
Authors: Mohiuddin Chowdhury Abu Taiub Mohammed , Kamal Aktar , Abbas Kafil Uddin , Talukder Shubhashis , Karim Md Rezaul , Ali Md. Ahsan , Nuruzzaman Md. , Li Yarui , He Shuixiang
Published: April 2022

Objective: In this study, we investigated the efficacy and safety of remdesivir and tocilizumab combination therapy against dexamethasone for the management of severe COVID-19 patients.

Methods: This was a multicenter study. Cases were randomly chosen and divided into two groups using an odd–even ratio of 1:1 applied to the hospital registration number. Group A received remdesivir [5 mg/kg (<40 kg) or 200 mg (>40 kg) on day 1 and then 2.5 mg/kg (<40 kg) or 100 mg (>40 kg) daily] + tocilizumab [8 mg/kg up to 800 mg highest 12 h apart], and group B was the control and received dexamethasone 6 mg/day. In addition, a broad-spectrum antibiotic and other essential treatments were received by all patients. To evaluate the mortality risk, the sequential organ failure assessment (SOFA) score was calculated on day-1. Treatment outcomes were measured as time to clinical improvement; mortality rate; duration of ICU stay; total period of hospitalization; the rate of (Supplementary Material) oxygen use; time to clinical failure; National Early Warning Score-2 (NEWS), and the percentage of lung recovery on CT of chest on discharge. Clinical trial registration ID: NCT04678739.

Results: Remdesivir-Tocilizumab group had a lower mortality rate (25.49%) than the control (30.77%). The time to clinical improvement (Group A-9.41; B-14.21 days), NEWS-2 on discharge (Group A-0.89; B-1.2), duration of ICU stay (Group A-7.68; B-10.58), and duration of hospitalization (Group A-9.91; B-14.68) were less in the treatment group. Group A had a better percentage of lung recovery on chest CT than the control (Group A-22.13; B-11.74). All these differences were statistically significant (p= <0.05) in a t-test. However, no significant survival benefit was found among the study groups in Kaplan–Meier survival analysis, p = 0.739.

Conclusion: The remdesivir–tocilizumab combination had preferable outcomes compared to the dexamethasone therapy for the treatment of severe COVID-19 concerning mortality rate and clinical and pulmonary improvement, although it did not demonstrate a significant survival benefit.

Clinical Trial Registration:https://clinicaltrials.gov, NCT04678739.
Impact of Three Safety Interventions Targeting Off-Label Use of Immediate-Release Fentanyl on Prescription Trends: Interrupted Time Series Analysis
Authors: García-Sempere Aníbal , Hurtado Isabel , Peiró Salvador , Sánchez-Sáez Francisco , Rodríguez-Bernal Clara Liliana , Puig-Ferrer Magda , Escolano Manuel , Sanfélix-Gimeno Gabriel
Published: April 2022

Background: The Spanish health authorities are concerned by the off-label use of immediate-release formulations of fentanyl (IRF) in noncancer pain and cancer pain in patients with no chronic pain therapy.

Aim: To evaluate the impact of different interventions to improve appropriateness of IRF prescription on off-label prescription.

Patients and methods: We used interrupted time series (ITS) to estimate immediate and trend changes of IRF prescription for noncancer pain (NCP) and breakthrough cancer pain (BCP) in patients with and without chronic cancer pain therapy associated with two medication reviews (I1 and I2) and the issue of a safety warning letter (I3) with data from a Spanish region with 5 million inhabitants, from 2015 to 2018.

Results: The use of IRF for NCP in the region Valencia was reduced from about 1,800 prescriptions per week to around 1,400. The first medication review was followed by an immediate level change of −192.66 prescriptions per week (p < 0.001) and a downward trend change of −6.75 prescriptions/week (p < 0.001), resulting in a post-intervention trend of −1.99 (p < 0.001). I2 was associated with a trend change of -23.07 (p < 0.001) prescriptions/week. After I3, the trend changed markedly to 27.23 additional prescriptions/week, for a final post-intervention trend of 2.17 (p < 0.001). Controlled-ITS provided comparable results. For potentially inappropriate BCP use, the second medication review was followed by a downward, immediate level change of −10.10 prescriptions/week (p = 0.011) and a trend change of 2.31 additional prescriptions/week (p < 0.001) and the issue of the safety warning (I3) was followed by a downward trend change of −2.09 prescriptions/week (p = 0.007).

Conclusion: Despite IRF prescription for NCP decreased, the interventions showed modest and temporary effect on off-label prescription. Our results call for a review of the design and implementation of safety interventions addressing inappropriate opioid use.
Registered Clinical Trials Comprising Pregnant Women in China: A Cross-Sectional Study
Authors: Zhao Yi , Du Guiping , Luan Xiaofei , Yang Hui , Zhang Qiongguang , Zhang Zhengfu , Wang Subiao
Published: April 2022

Background: In this study, an investigation was conducted on clinical drug trials comprising pregnant women in China that provided data on the quantity, properties, source of funding, and geographical distribution regarding registration and post-marketing studies.

Methods: We conducted a cross-sectional descriptive study of clinical trials of pregnant women in China on 30 December 2021, and it was registered on the official Drug Clinical Trial Information Management Platform (ChiCTR) (http://www.chinadrugtrials.org.cn) established by the State Food and Drug Administration of China (Chinese FDA).

Results: This study encompassed 72 registered trials (0.46%, 72/15,539) for data analysis. Of these trials, 43.1% of trials were started between 2013 and 2016, and nearly half of the trials (48.6%) were completed. Industries were listed as the primary sponsor for 95.8% trials. Economically developed eastern China and northern China, accounting for 69.5% of the 72 registered trials, were the most frequently identified study locations. Regarding study designs of these trials, more than half of the trials (70.8%) were randomized, 61.1% were a parallel assignment, 33.3% were phase 3, and half of the trials (54.2%) were open label. In total, 23 trials met the requirements after excluding trials of cancer and/or of postmenopausal women, accounting for 0.15% of the 15,539 registered trials in the ChiCTR websites. Of the 72 clinical trials, 54 drugs for 18 indications were included. Of these indications, the highest proportion of the trials is osteoporosis (27.8%), followed by cancer (22.2%), assisted reproduction (13.9%), and other indications (13.9%).

Conclusion: This survey revealed a significant shortage of the development, evaluation, and safety trials of pregnancy-related drugs in China. Modifying or adding legislation and providing financial incentives may therefore encourage pharmaceutical companies to conduct additional clinical trials on pregnant women.
New Therapeutic Horizon of Graves’ Hyperthyroidism: Treatment Regimens Based on Immunology and Ingredients From Traditional Chinese Medicine
Authors: He Qiongyao , Dong Hui , Gong Minmin , Guo Yujin , Xia Qingsong , Gong Jing , Lu Fuer
Published: April 2022

Graves’ disease is an autoimmune disease characterized by goiter and hyperthyroidism, and 25% patients develop GO. Traditional treatment options, such as antithyroid drugs, radioiodine or thyroidectomy, have remained largely unchanged over the past 70 years. For many patients, there is a high rate of recurrence after antithyroid drugs and lifelong hypothyroidism after ablation and thyroidectomy. The symptoms and quality of life of some patients have not been effectively improved. The clinical demand for new therapeutic regimens, coupled with a deeper understanding of the pathophysiology and immunobiology of Graves’ disease, has led to the emergence of several new therapeutic ideas, including biologics, small molecule peptides, immunomodulators and teprotumumab, a specific antibody targeting IGF-1R. Besides, the elements of TCM have attracted more and more interests in modern medicine, because some effective components have been successfully used in the treatment of autoimmune diseases. Based on the pathophysiology and efficacy of clinical management and treatment in Graves’ hyperthyroidism, here we review the new strategies under investigation and summarize the effective components of traditional Chinese medicine used for Graves’ hyperthyroidism, and explore their mechanisms. These therapies have opened a new window for the treatment of Graves’ disease, but the exact mechanism and the research direction still need to be further explored.
Meldonium Ameliorates Hypoxia-Induced Lung Injury and Oxidative Stress by Regulating Platelet-Type Phosphofructokinase-Mediated Glycolysis
Authors: Wang Daohui , Liu Fengying , Yang Weijie , Sun Yangyang , Wang Xiaoning , Sui Xin , Yang Jun , Wang Qian , Song Wenhao , Zhang Minmin , Xiao Zhenyu , Wang Tian , Wang Yongan , Luo Yuan
Published: April 2022

Hypoxic environments at high altitudes influence the long-term non-altitude health of residents, by inducing changes in metabolism and the mitochondria, severe lung injury, and endangering life. This study was aimed to determine whether meldonium can ameliorate hypoxia-induced lung injury and investigate its possible molecular mechanisms. We used Swiss mice and exposed type Ⅱ alveolar epithelial cell to hypobaric hypoxic conditions to induce lung injury and found that meldonium has significant preventive effect, which was associated with the regulation of glycolysis. We found using human proteome microarrays assay, molecular docking, immunofluorescence and pull-down assay that the target protein of meldonium is a platelet-type phosphofructokinase (PFKP), which is a rate-limiting enzyme of glycolysis. Also, meldonium promotes the transfer of nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, which mitigates oxidative stress and mitochondrial damage under hypoxic condition. Mechanistically, meldonium ameliorates lung injury by targeting PFKP to regulate glycolysis, which promotes Nrf2 translocation from the cytoplasm to the nucleus to alleviate oxidative stress and mitochondrial damage under hypoxic condition. Our study provides a novel potential prevention and treatment strategy against hypoxia-induced lung injury.
Gut Microbiota Metabolism of Azathioprine: A New Hallmark for Personalized Drug-Targeted Therapy of Chronic Inflammatory Bowel Disease
Authors: Lazarević Slavica , Đanic Maja , Al-Salami Hani , Mooranian Armin , Mikov Momir
Published: April 2022

Despite the growing number of new drugs approved for the treatment of inflammatory bowel disease (IBD), the long-term clinical use of thiopurine therapy and the well-known properties of conventional drugs including azathioprine have made their place in IBD therapy extremely valuable. Despite the fact that thiopurine S-methyltransferase (TPMT) polymorphism has been recognized as a major cause of the interindividual variability in the azathioprine response, recent evidence suggests that there might be some yet unknown causes which complicate dosing strategies causing either failure of therapy or toxicity. Increasing evidence suggests that gut microbiota, with its ability to release microbial enzymes, affects the pharmacokinetics of numerous drugs and subsequently drastically alters clinical effectiveness. Azathioprine, as an orally administered drug which has a complex metabolic pathway, is the prime illustrative candidate for such microbial metabolism of drugs. Comprehensive databases on microbial drug-metabolizing enzymes have not yet been generated. This study provides insights into the current evidence on microbiota-mediated metabolism of azathioprine and systematically accumulates findings of bacteria that possess enzymes required for the azathioprine biotransformation. Additionally, it proposes concepts for the identification of gut bacteria species responsible for the metabolism of azathioprine that could aid in the prediction of dose-response effects, complementing pharmacogenetic approaches already applied in the optimization of thiopurine therapy of IBD. It would be of great importance to elucidate to what extent microbiota-mediated metabolism of azathioprine contributes to the drug outcomes in IBD patients which could facilitate the clinical implementation of novel tools for personalized thiopurine treatment of IBD.
Non-targeted Metabolomics Analysis Based on LC–MS to Assess the Effects of Different Cold Exposure Times on Piglets
Authors: Chen Yong , Ji Hong , Guo Jingru , Chen Yan , Li Wenjie , Wang Shengping , Zhen Li
Published: April 2022

Pigs are susceptible to low temperature conditions, and cold stress causes metabolic changes in the body to increase heat production as an adaption to adverse environments. To characterize and validate different metabolites in piglet livers at different cold exposure times, sixteen 30-day-old male weaned piglets with similar weights were randomly divided into four groups: the normal temperature group (24 ± 2°C, NT) and cold exposure (4 ± 2°C) 2-h group (CS2), 6-h group (CS6), and 12-h group (CS12). At the end of the experiment, the liver samples were analyzed using systemic non-targeted metabolomics. Eight known differentially abundant metabolites (farnesyl pyrophosphate, isocitrate, triethanolamine, phenylethylamine, deoxynosine, citric acid, maltotriose, and epinephrine) were observed between the CS groups and the control group in positive and negative ion modes. The eight main differentially abundant metabolites involved in seven metabolite classifications. Metabolic pathways and enrichment analyses revealed that the pathways involved three KEGG pathway classifications. Most of the pathways were related to amino acid or energy metabolism. Moreover, the metabolic pathways were not identical under different cold exposure times, with those following 2 and 6 h of cold exposure more related to carbohydrates and energy production and those following 12 h of cold exposure more related to the metabolism connected with epinephrine. Thus, under different cold exposure times, the metabolite profiles and metabolic pathways differed.
Resting State EEG Directed Functional Connectivity Unveils Changes in Motor Network Organization in Subacute Stroke Patients After Rehabilitation
Authors: Pirovano Ileana , Mastropietro Alfonso , Antonacci Yuri , Barà Chiara , Guanziroli Eleonora , Molteni Franco , Faes Luca , Rizzo Giovanna
Published: April 2022

Brain plasticity and functional reorganization are mechanisms behind functional motor recovery of patients after an ischemic stroke. The study of resting-state motor network functional connectivity by means of EEG proved to be useful in investigating changes occurring in the information flow and find correlation with motor function recovery. In the literature, most studies applying EEG to post-stroke patients investigated the undirected functional connectivity of interacting brain regions. Quite recently, works started to investigate the directionality of the connections and many approaches or features have been proposed, each of them being more suitable to describe different aspects, e.g., direct or indirect information flow between network nodes, the coupling strength or its characteristic oscillation frequency. Each work chose one specific measure, despite in literature there is not an agreed consensus, and the selection of the most appropriate measure is still an open issue. In an attempt to shed light on this methodological aspect, we propose here to combine the information of direct and indirect coupling provided by two frequency-domain measures based on Granger’s causality, i.e., the directed coherence (DC) and the generalized partial directed coherence (gPDC), to investigate the longitudinal changes of resting-state directed connectivity associated with sensorimotor rhythms α and β, occurring in 18 sub-acute ischemic stroke patients who followed a rehabilitation treatment. Our results showed a relevant role of the information flow through the pre-motor regions in the reorganization of the motor network after the rehabilitation in the sub-acute stage. In particular, DC highlighted an increase in intra-hemispheric coupling strength between pre-motor and primary motor areas, especially in ipsi-lesional hemisphere in both α and β frequency bands, whereas gPDC was more sensitive in the detection of those connection whose variation was mostly represented within the population. A decreased causal flow from contra-lesional premotor cortex towards supplementary motor area was detected in both α and β frequency bands and a significant reinforced inter-hemispheric connection from ipsi to contra-lesional pre-motor cortex was observed in β frequency. Interestingly, the connection from contra towards ipsilesional pre-motor area correlated with upper limb motor recovery in α band. The usage of two different measures of directed connectivity allowed a better comprehension of those coupling changes between brain motor regions, either direct or mediated, which mostly were influenced by the rehabilitation, revealing a particular involvement of the pre-motor areas in the cerebral functional reorganization.
CRISPR/Cas9-Mediated Disruption of Xylanase inhibitor protein (XIP) Gene Improved the Dough Quality of Common Wheat
Authors: Sun Zhengjuan , Zhang Mingxia , An Yanrong , Han Xu , Guo Baojin , Lv Guangde , Zhao Yan , Guo Ying , Li Sishen
Published: April 2022

The wheat dough quality is of great significance for the end-use of flour. Some genes have been cloned for controlling the protein fractions, grain protein content, starch synthase, grain hardness, etc. Using a unigene map of the recombinant inbred lines (RILs) for “TN 18 × LM 6,” we mapped a quantitative trait locus (QTL) for dough stability time (ST) and SDS-sedimentation values (SV) on chromosome 6A (QSt/Sv-6A-2851). The peak position of the QTL covered two candidate unigenes, and we speculated that TraesCS6A02G077000 (a xylanase inhibitor protein) was the primary candidate gene (named the TaXip gene). The target loci containing the three homologous genes TaXip-6A, TaXip-6B, and TaXip-6D were edited in the variety “Fielder” by clustered regularly interspaced short palindromic repeats–associated protein 9 (CRISPR/Cas9). Two mutant types in the T2:3 generation were obtained (aaBBDD and AAbbdd) with about 120 plants per type. The SVs of aaBBDD, AAbbdd, and WT were 31.77, 27.30, and 20.08 ml, respectively. The SVs of the aaBBDD and AAbbdd were all significantly higher than those of the wild type (WT), and the aaBBDD was significantly higher than the AAbbdd. The STs of aaBBDD, AAbbdd, and WT were 2.60, 2.24, and 2.25 min, respectively. The ST for the aaBBDD was significantly higher than that for WT and was not significantly different between WT and AAbbdd. The above results indicated that XIP in vivo can significantly affect wheat dough quality. The selection of TaXip gene should be a new strategy for developing high-quality varieties in wheat breeding programs.
Developing Scotland’s First Green Health Prescription Pathway: A One-Stop Shop for Nature-Based Intervention Referrals
Authors: Marx Viola , More Kimberly R.
Published: April 2022

Introduction

Lifestyle modifications are part of comprehensive treatment plans to help manage the symptoms of pre-existing chronic conditions. However, behavior change is notoriously difficult as patients often lack the necessary support. The present manuscript outlines the development of a Green Health Prescription pathway that was designed to link patients with appropriate lifestyle interventions (i.e., nature-based interventions) and to support attendance. Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis was undertaken in three focus groups (i.e., National Health Service healthcare professionals, service-users, and nature-based intervention delivery partners) to highlight areas of strength and weakness within the proposed pathway prior to delivery. The SWOT analyses revealed that the pathway was supported by all three focus groups. Weaknesses and threats were identified including sustainability of nature-based interventions in terms of funding, the need to connect patients with appropriate interventions based on their physical and mental health needs, and the requirement to have a “one-stop shop” for information to ensure that the pathway was accessible for all service-users and healthcare professionals. Results were addressed and considered throughout the development of the pathway.

Discussion

The Green Health Prescription pathway was launched in 2019 and gave patients the ability to receive a prescription from a healthcare professional, community service, or to self-refer. The pathway allows patients to contact a consultant, via a telephone service, who is trained to match them with a programme that the patient believes will be enjoyable and that fits their treatment needs. Data collection to assess the efficacy of the pathway is ongoing.
Consequences, Motives, and Expectancies of Consumption as Predictors of Binge Drinking in University Women
Authors: Cortés-Tomás María-Teresa , Giménez-Costa José-Antonio , Motos-Sellés Patricia , Sancerni-Beitia María-Dolores
Published: April 2022

The increasing presence of women, especially university women, in risky alcohol consumption such as Binge Drinking (BD), which is associated with gender-specific biopsychosocial problems, makes it necessary to analyze the variables underlying BD in order to adjust possible interventions more in line with their reality. The motives and expectancies of this pattern of consumption, as well as the consequences derived from it, are some of the variables that are shown to have the greatest weight in the prediction of BD. In the present study we analyze, on the one hand, the performance of these variables among college women with alcohol use, and on the other hand, which of these variables allow us to classify BD. A total of 501 female university consumers of alcohol (mean age 19.02 years) were assessed. Specifically, they completed a self-report of alcohol consumption (77.1% engage in BD), the Expectancy Questionnaire (EQ), the Drinking Motives Questionnaire (DMQ-R) and the Alcohol Consumption Consequences Evaluation (ACCE). BD female students scored significantly higher on these instruments, except for compliance motives. The logistic regression analysis carried out to estimate the probability of performing BD using the social and conformity motives, the ACCE and positive expectancies correctly estimated (χ28 = 9.149, p < 0.33) 88.6% of the cases and explained 26.2% of the BD. Thus, young women with a level of consequences classified as high risk (>25 in ACCE) have a 3.55-fold increase in the probability of having BD, compared to women classified as low risk by the ACCE. On the other hand, women classified as moderate risk by the ACCE have a 4.77-fold increase in the probability of having BD. In the case of social motives and positive expectancies, their increase multiplies by 1.165 and 1.024, respectively, the probability of having BD. The results of this study highlight the importance of adapting preventive measures to the consequences experienced by BD university students, especially in relation to the social motives and positive expectancies that modulate decision-making when engaging in this pattern of consumption.
Empathic Narrative of Online Political Communication
Authors: Wang Yuqi , Lu Lihong , Zhou Zhibo , Zhu Jing
Published: April 2022

With the rapid development of the Internet, political culture plays an increasingly prominent role in ethical guidance and value orientation, and the intergenerational inheritance of political culture in various countries needs to be carried out in a sophisticated way. From the perspective of empathic narrative, this study applies the network text analysis method to detect the cultural communication regularities to the contemporary young adults in online political communication and explores contemporary young adults’ perception of online political culture through empirical analysis. Moreover, it proposes the empathic narrative logic of online political communication by comparing the existing communication elements and the urgently needed communication elements. Our findings suggest that we need to deepen the cognitive empathy, stabilize the emotional empathy, and adjust the emotional bias in online political communication.
Research on the Influence Mechanism of Consumers’ Perceived Risk on the Advertising Avoidance Behavior of Online Targeted Advertising
Authors: Wang Hai Jian , Yue Xia Lei , Ansari Aisha Rehman , Tang Gui Qian , Ding Jian Yi , Jiang Ya Qiong
Published: April 2022

In China, online sales continue to grow against the generally adverse effects of the COVID-19 pandemic on economic development. Although advertisers favor online targeted advertising for its precision, consumers may find it intrusive and avoid it. This study constructed a conceptual model based on Stimulus-Organism-Response (SOR) theory, Approach-Avoidance Theory, and Brand Avoidance Theory to investigate the influence mechanism of consumers’ perceived risk on the avoidance behavior of online targeted advertising via an online survey. Collected 436 validated data was analyzed through structural equation method in AMOS statistical software. Results showed that the positively influenced advertising avoidance, and negative emotions mediated the relationship between perceived performance risk, time-loss risk, freedom risk, and advertising avoidance, but perceived privacy risk did not influence advertising avoidance through negative emotions. Perceived COVID-19 risk moderates the effect of negative emotions on advertising avoidance. The findings provide important insights for helping governments, advertisers and online platforms into which risk perceptions influence advertising avoidance, and suggests ways to mitigate consumers risk perceptions for the mutual benefit of brands and users.