bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Coronavirus Disease 2019 Pandemic on Pediatric Out-of-Hospital Cardiac Arrest in the Emergency Department
Authors: Chen Chun-Yu , Lee En-Pei , Chang Yu-Jun , Yang Wen-Chieh , Lin Mao-Jen , Wu Han-Ping
Published: April 2022

Background

Out-of-hospital cardiac arrest (OHCA) in children is a critical condition with a poor prognosis. After the coronavirus disease 2019 (COVID-19) pandemic developed, the epidemiology and clinical characteristics of the pediatric emergency department (PED) visits have changed. This study aimed to analyze the impact of the COVID-19 pandemic on pediatric OHCA in the PED.

Methods

From January 2018 to September 2021, we retrospectively collected data of children (18 years or younger) with a definite diagnosis of OHCA admitted to the PED. Patient data studied included demographics, pre-/in-hospital information, treatment modalities; and outcomes of interest included sustained return of spontaneous circulation (SROSC) and survival to hospital-discharge (STHD). These were analyzed and compared between the periods before and after the COVID-19 pandemic.

Results

A total of 97 patients with OHCA (68 boys and 29 girls) sent to the PED were enrolled in our study. Sixty cases (61.9%) occurred in the pre-pandemic period and 37 during the pandemic. The most common age group was infants (40.2%) (p = 0.018). Asystole was the most predominant cardiac rhythm (72.2%, P = 0.048). Eighty patients (82.5%) were transferred by the emergency medical services, 62 (63.9%) gained SROSC, and 25 (25.8%) were STHD. During the COVID-19 pandemic, children with non-trauma OHCA had significantly shorter survival duration and prolonged EMS scene intervals (both p < 0.05).

Conclusion

During the COVID-19 pandemic, children with OHCA had a significantly lower rate of SROSC and STHD than that in the pre-pandemic period. The COVID-19 pandemic has changed the nature of PED visits and has affected factors related to ROSC and STHD in pediatric OHCA.
The Impact of Time Interval Between First Extubation and Reintubation on Bronchopulmonary Dysplasia or Death in Very Low Birth Weight Infants
Authors: Li Jing , Zhang Jing , Hao Qingfei , Shen Ziyun , Du Yanna , Chen Haoming , Cheng Xiuyong
Published: April 2022

Objective

To explore the association between time from first extubation to reintubation and moderate-to-severe bronchopulmonary dysplasia (BPD) or death in very low birth weight infants.

Study Design

Infants weighing <1,500 g at birth, requiring mechanical ventilation, and undergoing their initial extubation were retrospectively included from January 2014 to December 2021. They were divided into the moderate-to-severe BPD/death group and the comparison group according to the incidence of moderate-to-severe BPD or death. We defined time to reintubation as the time interval between first extubation and reintubation. In a stepwise multivariate logistic regression analysis, we examined the association between time to reintubation and moderate-to-severe BPD/death using different observation windows after initial extubation (24-h intervals).

Results

A total of 244 infants were recruited, including 57 cases in the moderate-severe BPD/death group and 187 cases in the comparison group, and 93 (38.1%) cases were reintubated at least one time after their first extubation. Univariate analysis showed that reintubation rates within different observation windows in the moderate-to-severe BPD/death group were statistically significantly (p < 0.05) higher than those in the comparison group. Multivariate regression analysis showed that reintubation within observation windows 48 h or 72 h post-extubation was an independent risk factor in moderate-to-severe BPD/death and death, but not moderate-to-severe BPD. When the time window was 48 h, the probability of moderate-to-severe BPD/death [odds ratio (OR): 3.778, 95% confidence interval (CI): 1.293–11.039] or death (OR: 4.734, 95% CI: 1.158–19.354) was highest. While after extending the observation window to include reintubations after 72 h from initial extubation, reintubation was not associated with increased risk of moderate-to-severe BPD and/or death.

Conclusions

Not all reintubations conferred increased risks of BPD/death. Only reintubation within 72 h from initial extubation was independently associated with increased likelihood of moderate-to-severe BPD/death and death in very low birth weight infants, and reintubation within the first 48 h post-extubation posed the greatest risk.
Metabolomics Applied to Cord Serum in Preeclampsia Newborns: Implications for Neonatal Outcomes
Authors: Wang Xiaoxu , Liu Jieying , Hui Xiangyi , Song Yingna
Published: April 2022

Preeclampsia (PE) is one of the leading causes of maternal and perinatal morbidity and mortality. However, it is still uncertain how PE affects neonate metabolism. We conducted an untargeted metabolomics analysis of cord blood to explore the metabolic changes in PE neonates. Umbilical cord serum samples from neonates with preeclampsia (n = 29) and non-preeclampsia (non-PE) (n = 32) pregnancies were analyzed using the UHPLC-QE-MS metabolomic platform. Different metabolites were screened, and pathway analysis was conducted. A subgroup analysis was performed among PE neonates to compare the metabolome between appropriate-for-gestational-age infants (n = 21) and small-for-gestational-age (SGA) infants (n = 8). A total of 159 different metabolites were detected in PE and non-PE neonates. Creatinine, N4-acetylcytidine, sphingomyelin (D18:1/16:0), pseudouridine, uric acid, and indolelactic acid were the most significant differential metabolites in the cord serum of PE neonates. Differential metabolite levels were elevated in PE neonates and were involved in the following metabolic pathways: glycine, serine, and threonine metabolism; sphingolipid, glyoxylate, and dicarboxylate metabolism; and arginine biosynthesis. In PE neonates, SGA neonates showed increased levels of hexacosanoyl carnitine and decreased abundance of 3-hydroxybutyric acid and 3-sulfinoalanine. Taurine-related metabolism and ketone body-related pathways were mainly affected. Based on the UHPLC-QE-MS metabolomics analysis, we identified the metabolic profiles of PE and SGA neonates. The abundance of metabolites related to certain amino acid, sphingolipid, and energy metabolism increased in the umbilical cord serum of PE neonates.
Nasal Continuous Positive Airway Pressure vs. Nasal Intermittent Positive Pressure Ventilation as Initial Treatment After Birth in Extremely Preterm Infants
Authors: Kostekci Yasemin Ezgi , Okulu Emel , Bakirarar Batuhan , Kraja Elvis , Erdeve Omer , Atasay Begum , Arsan Saadet
Published: April 2022

Objective

Non-invasive respiratory support strategies are known to reduce the complications of invasive mechanical ventilation in preterm infants. Nasal continuous positive airway pressure (NCPAP) and nasal intermittent positive pressure ventilation (NIPPV) are commonly used ones. The recent meta-analyses indicated that early NIPPV did appear to be superior to NCPAP for decreasing respiratory failure and the need for intubation among preterm infants with respiratory distress syndrome (RDS). The aim of the study was to compare the short-term outcomes of extremely preterm infants who received NCPAP or NIPPV as an initial treatment of RDS.

Methods

This retrospective study included infants born before 29 weeks' gestation between 1 January 2018 and 31 December 2021 who received non-invasive respiratory support with NCPAP or NIPPV. For every infant included in the cohort, only the first episode of NCPAP or NIPPV as initial treatment was evaluated. The primary outcome was the need for intubation within 72 h, and the secondary outcomes were the need for intubation within 7 days, administration of surfactant, prematurity-related morbidities, mortality, and death or bronchopulmonary dysplasia (BPD).

Results

During the study period, there were 116 inborn admissions of preterm infants born <29 weeks' gestation and 60 of them met the inclusion criteria. Of these, 31 (52%) infants received NCPAP while 29 (48%) infants received NIPPV at the first hours after birth. There were no differences in the baseline demographics between the groups (p > 0.05). Blood gas parameters (pH, pCO2, HCO3, and lactate) at admission were not different. The need for intubation within 72 h as the primary outcome was similar between NCPAP and NIPPV groups (35.5 vs. 34.5%, p = 0.935). The rates of surfactant requirement, need for intubation within 7 days, prematurity-related morbidities, mortality, and death/BPD were similar among the groups (p > 0.05).

Conclusion

Nasal intermittent positive pressure ventilation is non-inferior to NCPAP as an initial treatment in extremely preterm infants with RDS. Although the rate of intubation in the first week, mortality, and BPD did not differ between groups, additional studies are needed and the synchronization of NIPPV should be evaluated.
Phenethylisothiocyanate Potentiates Platinum Therapy by Reversing Cisplatin Resistance in Cervical Cancer
Authors: Mahapatra Elizabeth , Sengupta Debomita , Kumar Ravindra , Dehury Budheswar , Das Salini , Roy Madhumita , Mukherjee Sutapa
Published: April 2022

Acquired cisplatin resistance in cervical cancer therapy is principally caused by reduction in intracellular drug accumulation, which is exerted by hyperactivation of the oncogenic PI3K/Akt signaling axis and overexpression of cisplatin-exporter MRP2 along with prosurvival effectors NF-κB and IAPs in cervical cancer cells. These activated prosurvival signaling cascades drive drug efflux and evasion of apoptosis for rendering drug-resistant phenotypes. Our study challenges the PI3K/Akt axis in a cisplatin-resistant cervical cancer scenario with phenethylisothiocyanate (PEITC) for chemosensitization of SiHaR, a cisplatin-resistant sub-line of SiHa and 3-methylcholanthrene–induced cervical cancer mice models. SiHaR exhibited higher MRP2, p-AktThr308, NF-κB, XIAP, and survivin expressions which cumulatively compromised cisplatin retention capacity and accumulated PEITC better than SiHa. SiHaR appeared to favor PEITC uptake as its accumulation rates were found to be positively correlated with MRP2 expressions. PEITC treatment in SiHaR for 3 h prior to cisplatin exposure revived intracellular platinum levels, reduced free GSH levels, generated greater ROS, and altered mitochondrial membrane potential compared to SiHa. Western blot and immunofluorescence results indicated that PEITC successfully downregulated MRP2 in addition to suppressing p-AktThr308, XIAP, survivin, and NF-κB expressions. In mice models, administration of 5 mg/kg body-weight PEITC priming dosage prior to treatment with 3 mg/kg body-weight of cisplatin remediated cervical histology and induced tumor regression in contrast to the group receiving the same dosage of cisplatin only. This suggested PEITC as a potential chemosensitizing agent in light of acquired cisplatin resistance in cervical cancer and established its candidature for Phase I clinical trial.
Evaluation of Factors Associated With Appropriate Drug Prescription and Effectiveness of Informative and Educational Interventions—The EDU.RE.DRUG Project
Authors: Galimberti Federica , Olmastroni Elena , Casula Manuela , Merlo Ivan , Franchi Matteo , Catapano Alberico Luigi , Orlando Valentina , Menditto Enrica , Tragni Elena , EDU.RE.DRUG Group on behalf of
Published: April 2022

Background: EDU.RE.DRUG study is a prospective, multicentre, open-label, parallel-arm, controlled, pragmatic trial directed to general practitioners (GPs) and their patients.

Methods: The study data were retrieved from health-related administrative databases of four local health units (LHUs) of Lombardy and four LHUs in Campania. According to the LHUs, the GPs/patients were assigned to (A) intervention on both GPs (feedback reports about appropriate prescribing among their patients and online courses) and patients (flyers and posters on proper drug use), (B) intervention on GPs, (C) intervention on patients, and (D) no intervention (control arm). A set of appropriate prescribing indicators (potential drug–drug interactions [pDDIs], potential and unnecessary therapeutic duplicates [pTDs], and inappropriate prescriptions in the elderly [ERD-list]) were measured at baseline and after the intervention phase. The effectiveness of the intervention was evaluated estimating the absolute difference in percentages of selected indicators carrying out linear random-intercept mixed-effect models.

Results: A cohort of 3,586 GPs (2,567 in intervention groups and 1,019 in the control group) was evaluated. In Campania, the mean pre-intervention percentage of patients with at least one pDDI was always greater than 20% and always lower than 15% in Lombardy. The pre–post difference was quite heterogeneous among the LHUs, ranging from 1.9 to −1.4 percentage points. The mean pre-intervention percentage of patients with pTDs ranged from 0.59 to 2.1%, with slightly higher values characterizing Campania LHUs. The magnitude of the pre–post difference was very low, ranging from −0.11 to 0.20. In Campania, the mean pre-intervention percentage of patients with at least one ERD criterium was considerably higher than in Lombardy (approximately 30% in Lombardy and 50% in Campania). The pre–post difference was again quite heterogeneous. The results from the models accounting for GP geographical belonging suggested that none of the interventions resulted in a statistically significant effect, for all the three indicators considered.

Conclusion: The proposed strategy was shown to be not effective in influencing the voluntary changes in GP prescription performance. However, the use of a set of explicit indicators proved to be useful in quantifying the inappropriateness. Further efforts are needed to find more efficient strategies and design more tailored interventions.
Effectiveness and Safety of Anti-CD19 Chimeric Antigen Receptor-T Cell Immunotherapy in Patients With Relapsed/Refractory Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis
Authors: Ying Zhitao , Song Yuqin , Zhu Jun
Published: April 2022

Aim:To investigate the effectiveness and safety of using chimeric antigen receptor (CAR) T cell therapies targeting CD19 in patients with diffuse large B-cell lymphoma (DLBCL).

Methods:PubMed, Embase, and the Cochrane Library were searched for reports published from database inception up to July 2021. The present meta-analysis included clinical response outcomes, survival outcomes, and safety analyses. For qualitative analysis that could not be combined, the data were presented in a tabular form. Subgroup analyses were also performed according to the costimulatory domains, generic names, and study designs.

Results:Twenty-seven studies (1,687 patients) were included. The pooled 12-months overall survival (OS) rate was 63% (95%CI: 56–70%). The pooled best overall response (BOR) was 74.0% (95%CI: 67–79%), with a best complete response (BCR) of 48% (95%CI: 42–54%) and a 3-months CR rate (CRR) of 41% (95%CI: 35–47%). The subgroup analyses by costimulatory domain suggested statistically significant differences in BOR and BCR, whereas not in the 12-months OS rate and 3-months CRR. Among the patients evaluable for safety, 78% (95%CI: 68–87%), 6% (95%CI: 3–10%), 41% (95%CI: 31–52%), and 16% (95%CI: 10–24%) experienced cytokine release syndrome (CRS), severe CRS, neurotoxicity, and severe neurotoxicity, respectively. Compared with the CD28 costimulatory domain, the 4-1BB-based products showed a better safety profile on any-grade CRS (p< 0.01), severe CRS (p= 0.04), any-grade neurotoxicity (p< 0.01), and severe neurotoxicity (p< 0.01).

Conclusion:Anti-CD19 CAR-T cell immunotherapy has promising effectiveness and tolerable severe AE profile in DLBCL patients. 4-1BB-based CAR-T cells have a similar 12-months OS rate and 3-months CRR with CD28-based products but a better safety profile. The costimulatory domain might not affect the survival outcomes.
Pregnancy and Neonatal Outcomes After Exposure to Alprazolam in Pregnancy
Authors: Lee Hyunji , Koh Jae-Whoan , Kim Young-Ah , Chun Kyoung-Chul , Han Jung Yeol , Hwang Jong Hee , Choi June-Seek , Joo Sung Hong , Kwon Hye-Young
Published: April 2022

Alprazolam is a commonly prescribed benzodiazepine for anxiety or panic disorder, even in pregnant women. Information on the safety of alprazolam during pregnancy is insufficient. We aimed to evaluate pregnancy and neonatal outcomes after exposure to alprazolam during pregnancy. A prospective study was conducted on 725 pregnancies from January 2000 to December 2019. Participants were recruited through the Korean Mother-Safe Program, a service providing information on drug-induced teratogenic risk during pregnancy and breastfeeding. Exposed (N = 96) and non-exposed (N = 629) women to alprazolam during pregnancy were selected and followed-up until delivery. Pregnancy outcomes, including spontaneous abortion, still birth, low birth weight (LBW), preterm birth, Apgar score (at 1 and 5 min), and malformations were measured and compared. Multivariable logistic regression was performed to examine the association between alprazolam exposure and outcomes. The mean age was 32.9 (SD 4.0) years in the alprazolam-exposed group and 31.8 (SD 3.8) years in the unexposed group (p = 0.008). The alprazolam exposure group demonstrated a significantly higher likelihood of pregnancy and neonatal outcomes: spontaneous abortion (OR = 2.38; 95% CI 1.20–4.69), LBW (OR = 3.65; 95% CI 1.22–11.00), and Apgar score at 1 min ≤ 7 (OR = 2.19; 95% CI 1.02–4.67). There was no significant difference in congenital abnormalities between the exposure and non-exposure groups. Our findings confirmed that alprazolam exposure during pregnancy was significantly associated with adverse pregnancy and neonatal outcomes, including spontaneous abortion, low birth weight, and Apgar score at 1 min ≤ 7. Alprazolam during pregnancy should be appropriately regulated and monitored.
Minimal Physiologically-Based Pharmacokinetic (mPBPK) Metamodeling of Target Engagement in Skin Informs Anti-IL17A Drug Development in Psoriasis
Authors: Ayyar Vivaswath S. , Lee Jong Bong , Wang Weirong , Pryor Meghan , Zhuang Yanli , Wilde Thomas , Vermeulen An
Published: April 2022

The pharmacologic effect(s) of biotherapeutics directed against soluble targets are driven by the magnitude and duration of free target suppression at the tissue site(s) of action. Interleukin (IL)-17A is an inflammatory cytokine that plays a key role in the pathogenesis of psoriasis. In this work, clinical trial data from two monoclonal antibodies (mAbs) targeting IL-17A for treatment of psoriasis (secukinumab and ixekizumab) were analyzed simultaneously to quantitatively predict their target engagement (TE) profiles in psoriatic skin. First, a model-based meta-analysis (MBMA) for clinical responses was conducted separately for each drug based on dose. Next, a minimal physiologically-based pharmacokinetic (mPBPK) model was built to assess skin site IL-17A target engagement for ixekizumab and secukinumab simultaneously. The mPBPK model captured the observed drug PK, serum total IL-17A, and skin drug concentration-time profiles reasonably well across the different dosage regimens investigated. The developed mPBPK model was then used to predict the average TE (i.e., free IL-17A suppression) in skin achieved over a 12-weeks treatment period for each drug following their respective regimens and subsequently assess the TE-efficacy response relationship. It was predicted that secukinumab achieved 98.6% average TE in the skin at 300 mg q4w SC while ixekizumab achieved 99.9% average TE under 160 mg (loading) followed by 80 mg q2w SC. While direct quantification of free IL-17A levels at the site of action is technically challenging, integrated mPBPK-MBMA approaches offer quantitative predictions of free IL-17A levels at the site of action to facilitate future drug development via IL-17A suppression in psoriasis.
Clinical Intervention Increases Rational Use of Proton Pump Inhibitors in the General Surgery Department
Authors: Chen Qiying , Wang Qiaohong , Zhang Yin
Published: April 2022

This study aimed to evaluate the role of the clinical pharmacist in the rational use of proton pump inhibitors (PPIs) in a general surgery department. All enrolled patients had attended the general surgery department of a tertiary hospital. This single-center prospective study compared differences in the overall rate of rational PPI use, proportion of unindicated PPI use, utilization rate, average defined daily dose (DDD), drug costs, PPI costs, and cost-effectiveness of clinical pharmacist intervention between the intervention (538 cases) and control (536 cases) groups. In the intervention group, Pareto and fishbone diagram analyses were combined with the Plan-Do-Check-Act cycle; Statistical Package for the Social Sciences was used for analyzing all data. The overall rate of rational PPI use was significantly higher in the intervention group than in the control group (p < 0.01). The proportion of unindicated PPI use, utilization rate, average DDD, drug costs, and PPI costs were significantly lower in the intervention group than in the control group (p < 0.05). Cost-effectiveness analysis for the overall rate of rational PPI use indicated a positive impact of intervention, with economic benefits in the intervention group. Clinical pharmacist intervention for rational use of PPIs in general surgery departments could significantly increase the overall rate of rational PPI use; it could also reduce the proportion of unindicated PPI use, utilization rates, average DDDs, drug costs, and PPIs costs. Pharmacist intervention also offers economic benefits by improving the overall rate of rational PPI use.
Development of the Korean Medicine Core Outcome Set for Stroke Sequelae: Herbal Medicine Treatment of Elderly Patients With Stroke Sequelae in Primary Clinics
Authors: Cha Jiyun , Kim Sungha , Kim Pyung-Wha , Lee Hesol , Ko Mi Mi , Jang Soobin , Lee Myeong Soo
Published: April 2022

Objectives: We developed a Korean medicine core outcome set for stroke sequelae (COS-SS-KM) to evaluate the effectiveness and safety of herbal medicine (HM) for stroke sequelae, especially for elderly stroke patients in primary clinics.

Methods: We identified previously reported outcomes from a literature review and defined the list of outcomes and effect modifiers for the core outcome set (COS) questionnaire. Three rounds of modified Delphi consensus exercises with experts were conducted online for suitability assessment, and one round of a modified Delphi consensus exercise with primary clinicians was conducted for feasibility assessment.

Results: The review identified 17 outcomes and 16 effect modifiers; moreover, six outcomes and one effect modifier were suggested by the experts. The final COS comprised 8 outcomes and 12 effect modifiers for history taking, and experts listed 13 major symptoms of stroke sequelae for symptom assessment. The clinicians agreed on the feasibility of the COS.

Conclusion: This COS will help primary care researchers assess the effectiveness of pharmacotherapy, including HM, for elderly patients with stroke sequelae. Future studies should focus on reflecting the opinions of all stakeholders.
Arecoline Induces an Excitatory Response in Ventral Tegmental Area Dopaminergic Neurons in Anesthetized Rats
Authors: Lan Qinghui , Guan Peiqing , Huang Chunzheng , Huang Shile , Zhou Peiling , Zhang Changzheng
Published: April 2022

Arecoline is the principle psychoactive alkaloid in areca nuts. Areca nuts are chewable seeds of Areca catechu L., which are epidemic plants that grow in tropical and subtropical countries and cause dependency after long-term use. However, the mechanisms underlying such dependency remain largely unclear, and therefore, no effective interventions for its cessation have been developed. The present study aimed to examine the effects of arecoline on neurons of the ventral tegmental area (VTA). After rats were anesthetized and craniotomized, electrophysiological electrodes were lowered into the VTA to obtain extracellular recordings. The mean firing rate of dopaminergic and GABAergic neurons were then calculated and analyzed before and after arecoline treatment. The burst characteristics of the dopaminergic neurons were also analyzed. The results showed that arecoline evoked a significant enhancement of the firing rate of dopaminergic neurons, but not GABAergic neurons. Moreover, arecoline evoked remarkable burst firings in the dopaminergic neurons, including an increase in the burst rate, elongation in the burst duration, and an enhancement in the number of spikes per burst. Collectively, the findings revealed that arecoline significantly excited VTA dopaminergic neurons, which may be a mechanism underlying areca nut dependency and a potential target for areca nut cessation therapy.
An Updated Review of Genetic Associations With Severe Adverse Drug Reactions: Translation and Implementation of Pharmacogenomic Testing in Clinical Practice
Authors: Wang Chuang-Wei , Preclaro Ivan Arni C. , Lin Wei-Hsiang , Chung Wen-Hung
Published: April 2022

Adverse drug reactions (ADR) remain the major problems in healthcare. Most severe ADR are unpredictable, dose-independent and termed as type B idiosyncratic reactions. Recent pharmacogenomic studies have demonstrated the strong associations between severe ADR and genetic markers, including specific HLA alleles (e.g., HLA-B*15:02/HLA-B*57:01/HLA-A*31:01 for carbamazepine-induced severe cutaneous adverse drug reactions [SCAR], HLA-B*58:01 for allopurinol-SCAR, HLA-B*57:01 for abacavir-hypersensitivity, HLA-B*13:01 for dapsone/co-trimoxazole-induced SCAR, and HLA-A*33:01 for terbinafine-induced liver injury), drug metabolism enzymes (such as CYP2C9*3 for phenytoin-induced SCAR and missense variant of TPMT/NUDT15 for thiopurine-induced leukopenia), drug transporters (e.g., SLCO1B1 polymorphism for statin-induced myopathy), and T cell receptors (Sulfanilamide binding into the CDR3/Vα of the TCR 1.3). This mini review article aims to summarize the current knowledge of pharmacogenomics of severe ADR, and the potentially clinical use of these genetic markers for avoidance of ADR.
Cannabis for Medical Use: Versatile Plant Rather Than a Single Drug
Authors: Procaccia Shiri , Lewitus Gil Moshe , Lipson Feder Carni , Shapira Anna , Berman Paula , Meiri David
Published: April 2022

Medical Cannabis and its major cannabinoids (−)-trans-Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are gaining momentum for various medical purposes as their therapeutic qualities are becoming better established. However, studies regarding their efficacy are oftentimes inconclusive. This is chiefly because Cannabis is a versatile plant rather than a single drug and its effects do not depend only on the amount of THC and CBD. Hundreds of Cannabis cultivars and hybrids exist worldwide, each with a unique and distinct chemical profile. Most studies focus on THC and CBD, but these are just two of over 140 phytocannabinoids found in the plant in addition to a milieu of terpenoids, flavonoids and other compounds with potential therapeutic activities. Different plants contain a very different array of these metabolites in varying relative ratios, and it is the interplay between these molecules from the plant and the endocannabinoid system in the body that determines the ultimate therapeutic response and associated adverse effects. Here, we discuss how phytocannabinoid profiles differ between plants depending on the chemovar types, review the major factors that affect secondary metabolite accumulation in the plant including the genotype, growth conditions, processing, storage and the delivery route; and highlight how these factors make Cannabis treatment highly complex.
Stat3 Signaling Pathway: A Future Therapeutic Target for Bone-Related Diseases
Authors: Li Jiadong , Yin Zhifeng , Huang Biaotong , Xu Ke , Su Jiacan
Published: April 2022

Signal transducer and activator of transcription 3 (Stat3) is activated by phosphorylation and translocated to the nucleus to participate in the transcriptional regulation of DNA. Increasing evidences point that aberrant activation or deletion of the Stat3 plays a critical role in a broad range of pathological processes including immune escape, tumorigenesis, and inflammation. In the bone microenvironment, Stat3 acts as a common downstream response protein for multiple cytokines and is engaged in the modulation of cellular proliferation and intercellular interactions. Stat3 has direct impacts on disease progression by regulating mesenchymal stem cells differentiation, osteoclast activation, macrophage polarization, angiogenesis, and cartilage degradation. Here, we describe the theoretical basis and key roles of Stat3 in different bone-related diseases in combination with in vitro experiments and animal models. Then, we summarize and categorize the drugs that target Stat3, providing potential therapeutic strategies for their use in bone-related diseases. In conclusion, Stat3 could be a future target for bone-related diseases.
Differences in Behavioral Characteristics and Diffusion Mechanisms: A Comparative Analysis Based on Social Bots and Human Users
Authors: Cai Meng , Luo Han , Meng Xiao , Cui Ying
Published: April 2022

In the field of social media, the systematic impact that bot users bring to the dissemination of public opinion has been a key concern of the research. To achieve more effective opinion management, it is important to understand how and why behavior differs between bot users and human users. The study compares the differences in behavioral characteristics and diffusion mechanisms between bot users and human users during public opinion dissemination, using public health emergencies as the research target, and further provides specific explanations for the differences. First, the study classified users with bot characteristics and human users by establishing the relevant formulas of user indicator characteristics. Secondly, the study used deep learning methods such as Top2Vec and BERT to extract topics and sentiments, and used social network analysis methods to construct network graphs and compare network attribute features. Finally, the study further compared the differences in information dissemination between posts published by bot users and human users through multi-factor ANOVA. It was found that there were significant differences in behavioral characteristics and diffusion mechanisms between bot users and human users. The findings can help guide the public to pay attention to topic shifting and promote the diffusion of positive emotions in social networks, which in turn can better achieve emergency management of emergencies and the maintenance of online orders.
Electron Streaming Effect Associated With the Elekta Unity Anterior Imaging Coil
Authors: Powers Marcus , Baines John
Published: April 2022

The presence of the static field in magnetic resonance guided radiation therapy (MRgRT) systems, such as the Elekta Unity MR-Linac (MRL), influences charged particle motion due to the Lorentz force in and around patients. Consequently, for the Unity, changes to out-of-field dose (OFD) relative to conventional linacs occur due to the electron streaming effect (ESE) and spiraling contaminant electrons (SCE). This work investigates OFD associated with irradiation of the anterior MR imaging coil, which is in situ for all treatments on the Unity. Film measurements and Monaco simulations were performed to quantify the magnitude of OFD at the superior and inferior ends of the coil as a function of coil tilt relative to the beam direction. The dependence of OFD on field size and the relative electron density (RED) assigned to the coil and surrounding air are reported. The doses at both coil ends were clinically significant, with nearly 23.0% of the Dmax dose to water being recorded for the largest field (8.0 × 22.0 cm2) and 6.8% for the smallest field (3.0 × 3.0 cm2). Monaco simulations of OFD agreed with film within 5.0%, when appropriate calculation conditions were set. OFD decreases as coil tilt is reduced, and there is no evidence of ESE when the coil is horizontal. Clinically, the potential magnitude of cranio–caudal streaming dose from a tilted coil necessitates the use of appropriate shielding. A clinical case involving coil-induced ESE during treatment of a lesion in the right angle is presented. The planning-based investigation revealed that ESE doses associated with the coil and an immobilization vacuum bag can be clinically significant.
Robust Reconstruction of Electrocardiogram Using Photoplethysmography: A Subject-Based Model
Authors: Tang Qunfeng , Chen Zhencheng , Guo Yanke , Liang Yongbo , Ward Rabab , Menon Carlo , Elgendi Mohamed
Published: April 2022

Electrocardiography and photoplethysmography are non-invasive techniques that measure signals from the cardiovascular system. While the cycles of the two measurements are highly correlated, the correlation between the waveforms has rarely been studied. Measuring the photoplethysmogram (PPG) is much easier and more convenient than the electrocardiogram (ECG). Recent research has shown that PPG can be used to reconstruct the ECG, indicating that practitioners can gain a deep understanding of the patients’ cardiovascular health using two physiological signals (PPG and ECG) while measuring only PPG. This study proposes a subject-based deep learning model that reconstructs an ECG using a PPG and is based on the bidirectional long short-term memory model. Because the ECG waveform may vary from subject to subject, this model is subject-specific. The model was tested using 100 records from the MIMIC III database. Of these records, 50 had a circulatory disease. The results show that a long ECG signal could be effectively reconstructed from PPG, which is, to our knowledge, the first attempt in this field. A length of 228 s of ECG was constructed by the model, which was trained and validated using 60 s of PPG and ECG signals. To segment the data, a different approach that segments the data into short time segments of equal length (and that do not rely on beats and beat detection) was investigated. Segmenting the PPG and ECG time series data into equal segments of 1-min width gave the optimal results. This resulted in a high Pearson’s correlation coefficient between the reconstructed 228 s of ECG and referenced ECG of 0.818, while the root mean square error was only 0.083 mV, and the dynamic time warping distance was 2.12 mV per second on average.
It’s About Time: The Circadian Network as Time-Keeper for Cognitive Functioning, Locomotor Activity and Mental Health
Authors: Yalçin Müge , Mundorf Annakarina , Thiel Freya , Amatriain-Fernández Sandra , Kalthoff Ida Schulze , Beucke Jan-Carl , Budde Henning , Garthus-Niegel Susan , Peterburs Jutta , Relógio Angela
Published: April 2022

A variety of organisms including mammals have evolved a 24h, self-sustained timekeeping machinery known as the circadian clock (biological clock), which enables to anticipate, respond, and adapt to environmental influences such as the daily light and dark cycles. Proper functioning of the clock plays a pivotal role in the temporal regulation of a wide range of cellular, physiological, and behavioural processes. The disruption of circadian rhythms was found to be associated with the onset and progression of several pathologies including sleep and mental disorders, cancer, and neurodegeneration. Thus, the role of the circadian clock in health and disease, and its clinical applications, have gained increasing attention, but the exact mechanisms underlying temporal regulation require further work and the integration of evidence from different research fields. In this review, we address the current knowledge regarding the functioning of molecular circuits as generators of circadian rhythms and the essential role of circadian synchrony in a healthy organism. In particular, we discuss the role of circadian regulation in the context of behaviour and cognitive functioning, delineating how the loss of this tight interplay is linked to pathological development with a focus on mental disorders and neurodegeneration. We further describe emerging new aspects on the link between the circadian clock and physical exercise-induced cognitive functioning, and its current usage as circadian activator with a positive impact in delaying the progression of certain pathologies including neurodegeneration and brain-related disorders. Finally, we discuss recent epidemiological evidence pointing to an important role of the circadian clock in mental health.
Pro-Arrhythmic Effects of Discontinuous Conduction at the Purkinje Fiber-Ventricle Junction Arising From Heart Failure-Induced Ionic Remodeling – Insights From Computational Modelling
Authors: Jian Kun , Li Chen , Hancox Jules C. , Zhang Henggui
Published: April 2022

Heart failure is associated with electrical remodeling of the electrical properties and kinetics of the ion channels and transporters that are responsible for cardiac action potentials. However, it is still unclear whether heart failure-induced ionic remodeling can affect the conduction of excitation waves at the Purkinje fiber-ventricle junction contributing to pro-arrhythmic effects of heart failure, as the complexity of the heart impedes a detailed experimental analysis. The aim of this study was to employ computational models to investigate the pro-arrhythmic effects of heart failure-induced ionic remodeling on the cardiac action potentials and excitation wave conduction at the Purkinje fiber-ventricle junction. Single cell models of canine Purkinje fiber and ventricular myocytes were developed for control and heart failure. These single cell models were then incorporated into one-dimensional strand and three-dimensional wedge models to investigate the effects of heart failure-induced remodeling on propagation of action potentials in Purkinje fiber and ventricular tissue and at the Purkinje fiber-ventricle junction. This revealed that heart failure-induced ionic remodeling of Purkinje fiber and ventricular tissue reduced conduction safety and increased tissue vulnerability to the genesis of the unidirectional conduction block. This was marked at the Purkinje fiber-ventricle junction, forming a potential substrate for the genesis of conduction failure that led to re-entry. This study provides new insights into proarrhythmic consequences of heart failure-induced ionic remodeling.
Identification and Validation of Reference Genes for Gene Expression Analysis in Monochamus saltuarius Under Bursaphelenchus xylophilus Treatment
Authors: Li Jiaxing , Fu Ningning , Ren Lili , Luo Youqing
Published: April 2022

A special mutual relationship exists between the pine wood nematode (PWN) Bursaphelenchus xylophilus and its vector beetles of genus Monochamus, which enables PWN to spread, at the same time provides longhorned beetles with more weak hosts. PWN are attracted to the pupal chambers and then carried inside the trachea of beetle adults, which is a necessary part to complete the B. xylophilus infection cycle. The growth and immune responses of the vector beetle will affect this carrying process, however, they were rarely studied in Monochamus saltuarius. Real-time quantitative polymerase chain reaction (RT-qPCR), one of the most common methods for quantitative gene expression analysis, was performed to explore the key genes and pathways involved in the growth, development and immune responses of M. saltuarius at different developmental stages associated with infection of PWN and PWN treatment conditions. To enhance the accuracy of RT-qPCR data, the expression of target genes needs to be normalized with reference genes, which are stably expressed under varied experimental conditions. In our study, the stability of 14 candidate reference genes in M. saltuarius samples at different developmental stages associated with infection of PWN or PWN treatment conditions was evaluated using delta Ct, geNorm, NormFinder, BestKeeper and RefFinder algorithms. Moreover, KLF gene was used to validate the stability of the selected reference genes. Under experimental conditions of this study, RPL7 and TER were suitable reference genes at different developmental stages associated with infection of PWN. RPL7 and RPS5 were considered the most stable reference genes in the pupae treated with PWN. RPS5 and SNX6 could be used as reference genes in the adults treated with PWN. RPL7, EF1-γ, and RPS5 could be used as stable reference genes in all the samples. This work is the first to evaluate reference genes in M. saltuarius, laying a foundation for further gene expression experimental procedures and understanding the phoretic relationship between M. saltuarius and B. xylophilus.
Novel Genomic Regions Linked to Ascochyta Blight Resistance in Two Differentially Resistant Cultivars of Chickpea
Authors: Alo Fida , Rani Anupalli Roja , Baum Michael , Singh Sarvjeet , Kehel Zakaria , Rani Upasana , Udupa Sripada , Al-Sham’aa Khaled , Alsamman Alsamman M. , Istanbuli Tawffiq , Attar Basem , Hamwieh Aladdin , Amri Ahmed
Published: April 2022

Ascochyta blight (AB), caused by the fungal pathogen Ascochyta rabiei, is a devastating foliar disease of chickpea (Cicer arietinum L.). The genotyping-by-sequencing (GBS)-based approach was deployed for mapping QTLs associated with AB resistance in chickpea in two recombinant inbred line populations derived from two crosses (AB3279 derived from ILC 1929 × ILC 3279 and AB482 derived from ILC 1929 × ILC 482) and tested in six different environments. Twenty-one different genomic regions linked to AB resistance were identified in regions CalG02 and CalG04 in both populations AB3279 and AB482. These regions contain 1,118 SNPs significantly associated with AB resistance (p ≤ 0.001), which explained 11.2–39.3% of the phenotypic variation (PVE). Nine of the AB resistance-associated genomic regions were newly detected in this study, while twelve regions were known from previous AB studies. The proposed physical map narrows down AB resistance to consistent genomic regions identified across different environments. Gene ontology (GO) assigned these QTLs to 319 genes, many of which were associated with stress and disease resistance, and with most important genes belonging to resistance gene families such as leucine-rich repeat (LRR) and transcription factor families. Our results indicate that the flowering-associated gene GIGANTEA is a possible key factor in AB resistance in chickpea. The results have identified AB resistance-associated regions on the physical genetic map of chickpea and allowed for the identification of associated markers that will help in breeding of AB-resistant varieties.
Evolutionary Ecology of Plant-Arthropod Interactions in Light of the “Omics” Sciences: A Broad Guide
Authors: De-la-Cruz Ivan M. , Batsleer Femke , Bonte Dries , Diller Carolina , Hytönen Timo , Muola Anne , Osorio Sonia , Posé David , Vandegehuchte Martijn L. , Stenberg Johan A.
Published: April 2022

Aboveground plant-arthropod interactions are typically complex, involving herbivores, predators, pollinators, and various other guilds that can strongly affect plant fitness, directly or indirectly, and individually, synergistically, or antagonistically. However, little is known about how ongoing natural selection by these interacting guilds shapes the evolution of plants, i.e., how they affect the differential survival and reproduction of genotypes due to differences in phenotypes in an environment. Recent technological advances, including next-generation sequencing, metabolomics, and gene-editing technologies along with traditional experimental approaches (e.g., quantitative genetics experiments), have enabled far more comprehensive exploration of the genes and traits involved in complex ecological interactions. Connecting different levels of biological organization (genes to communities) will enhance the understanding of evolutionary interactions in complex communities, but this requires a multidisciplinary approach. Here, we review traditional and modern methods and concepts, then highlight future avenues for studying the evolution of plant-arthropod interactions (e.g., plant-herbivore-pollinator interactions). Besides promoting a fundamental understanding of plant-associated arthropod communities’ genetic background and evolution, such knowledge can also help address many current global environmental challenges.
Transcriptome Meta-Analysis Associated Targeting Hub Genes and Pathways of Drought and Salt Stress Responses in Cotton (Gossypium hirsutum): A Network Biology Approach
Authors: Bano Nasreen , Fakhrah Shafquat , Mohanty Chandra Sekhar , Bag Sumit Kumar
Published: April 2022

Abiotic stress tolerance is an intricate feature controlled through several genes and networks in the plant system. In abiotic stress, salt, and drought are well known to limit cotton productivity. Transcriptomics meta-analysis has arisen as a robust method to unravel the stress-responsive molecular network in crops. In order to understand drought and salt stress tolerance mechanisms, a meta-analysis of transcriptome studies is crucial. To confront these issues, here, we have given details of genes and networks associated with significant differential expression in response to salt and drought stress. The key regulatory hub genes of drought and salt stress conditions have notable associations with functional drought and salt stress-responsive (DSSR) genes. In the network study, nodulation signaling pathways 2 (NSP2), Dehydration-responsive element1 D (DRE1D), ethylene response factor (ERF61), cycling DOF factor 1 (CDF1), and tubby like protein 3 (TLP3) genes in drought and tubby like protein 1 (TLP1), thaumatin-like proteins (TLP), ethylene-responsive transcription factor ERF109 (EF109), ETS-Related transcription Factor (ELF4), andArabidopsis thalianahomeodomain leucine-zipper gene (ATHB7) genes in salt showed the significant putative functions and pathways related to providing tolerance against drought and salt stress conditions along with the significant expression values. These outcomes provide potential candidate genes for further in-depth functional studies in cotton, which could be useful for the selection of an improved genotype ofGossypium hirsutumagainst drought and salt stress conditions.