bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Use of the Target Trial Approach in Perinatal Pharmacoepidemiology: A Scoping Review Protocol
Authors: Leal Lisiane Freitas , Grandi Sonia Marzia , Mota Daniel Marques , Ferreira Paulo José Gonçalves , Gore Genevieve , Platt Robert William 
Published: July 2022

Background: Pregnant and postpartum women have been historically excluded from clinical trials, with data on the safety of drugs relying on observational research. Methodological concerns regarding the timing and dosing of medications, data sources, study designs, and methods used for estimating associations are still problematic in observational studies. Answering causal questions is even more complex. Despite the increased interest in emulating target trials using observational data, little is known about this approach in perinatal pharmacoepidemiology.Objective: This scoping review protocol aims to describe the methodology for assessing the available literature concerning emulating target trials for studying outcomes in women exposed to medications in the preconception, perinatal, or postpartum periods.Methods and Analysis: We will follow the methods detailed in the Joanna Briggs Institute reviewer’s manual. We will adopt the six-stage framework recommended by Arksey and O'Malley and Levac and others. Web scraping techniques will be used for identifying relevant studies. Two authors will select articles based on the title and abstract, with discrepancies resolved by consensus, by a third reviewer. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews flow diagram will be presented to reflect the search process. We will use existing statements to identify quality gaps in the current literature. Variables related to the content for perinatal pharmacoepidemiologic research will be included. The Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) will guide the assessment of the target trial emulation (i.e., treatment strategies compared, assignment procedures, follow-up period, outcome, and causal contrasts).Discussion: Data regarding the safety of drugs taken, prior to and during pregnancy and while lactating are lacking and it is necessary to understand how we can answer these questions using rigorous methods in observational research. Through this scoping review, we intend to understand to what extent the target trial approach is being used in perinatal pharmacoepidemiology and provide recommendations to improve its use in this field.Ethics and Dissemination: Secondary data from published scientific articles will be used, not requiring approval by the Research Ethics Committee with human beings. Findings will be submitted to a peer-reviewed journal.
Efficacy and safety of intravenous acetaminophen (2 g/day) for reducing opioid consumption in Chinese adults after elective orthopedic surgery: A multicenter randomized controlled trial
Authors: Yin Feng , Ma Wei , Liu Qiao , Xiong Liu-Lin , Wang Ting-Hua , Li Qian , Liu Fei 
Published: July 2022

Background: Acetaminophen is an important component of a multimodal analgesia strategy to reduce opioid consumption and pain intensity after an orthopedic surgery. The opioid-sparing efficacy of intravenous acetaminophen has been established at a daily dose of 4 g. However, it is still unclear for the daily dose of 2 g of acetaminophen, which is recommended by the China Food and Drug Administration Center for Drug Evaluation, in terms of its efficacy and safety.Objectives: This study aimed to evaluate the efficacy and safety of intravenous acetaminophen at a daily dose of 2 g for reducing opioid consumption and pain intensity after orthopedic surgery.Methods: In this multicenter, randomized, double-blind, placebo-controlled phase III trial, 235 patients who underwent orthopedic surgery were randomly assigned to receive intravenous acetaminophen 500 mg every 6 h or placebo. Postoperative morphine consumption, pain intensity at rest and during movement, and adverse events were analysed.Results: For the mean (standard deviation) morphine consumption within 24 h after surgery, intravenous acetaminophen was superior to placebo both in the modified intention-to-treat analysis [8.7 (7.7) mg vs. 11.2 (9.2) mg] in the acetaminophen group and the placebo group, respectively. Difference in means: 2.5 mg; 95% confidence interval, 0.25 to 4.61; p = 0.030), and in the per-protocol analysis (8.3 (7.0) mg and 11.7 (9.9) mg in the acetaminophen group and the placebo group, respectively. Difference in means: 3.4 mg; 95% confidence interval: 1.05 to 5.77; p = 0.005). The two groups did not differ significantly in terms of pain intensity and adverse events.Conclusion: Our results suggest that intravenous acetaminophen at a daily dose of 2 g can reduce morphine consumption by Chinese adults within the first 24 h after orthopedic surgery, but the extent of reduction is not clinically relevant.Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT02811991].
Flavonoid Group of Smilax glabra Roxb. Regulates the Anti-Tumor Immune Response Through the STAT3/HIF-1 Signaling Pathway
Authors: Guo Yingxue , Mao Weiye , Jin Lu , Xia Linying , Huang Jie , Liu Xia , Ni Ping , Shou Qiyang , Fu Huiying 
Published: July 2022

Background:Smilax glabra Roxb. (SGR) is a widely used traditional Chinese medicine, which has known effects of enhancing immunity. However, its anti-tumor effects and mechanism of action are still unclear.Methods: We selected MMTV-PyMT mice to determine the anti-tumor efficacy of SGR ethyl acetate (SGR-EA). First, flow cytometry was used to detect the number of immune cells in the mice tumor microenvironment. Furthermore, M2 polarization of macrophages was stimulated in vitro, and the expressions of macrophage M1/M2 surface markers and mRNA were as determined. Finally, we carried out a network pharmacology analysis on the active components of SGR-EA and in vitro experiments to verify that SGR-EA regulated the hypoxia-inducible factor (HIF)-1 signaling pathway to modulate the anti-tumor immune response by resetting M2 macrophages toward the M1 phenotype which inhibited tumor growth and lung metastasis in the mice.Result: SGR-EA inhibited tumor growth and lung metastasis in the mice. Tumor-associated macrophages switched from M2 to the tumor-killing M1 phenotype and promoted the recruitment of CD4+ and CD8+ T cells in the tumor microenvironment. In vitro, SGR-EA significantly inhibited the polarization of macrophages into M2 macrophages and increased the number of M1 macrophages. In addition, following an intervention with SGR-EA, the expression of the HIF-1 signaling pathway-related proteins stimulated by interleukin-4 in macrophages was significantly inhibited.Conclusion: SGR-EA played an anti-tumor role by inhibiting the activation of the HIF-1 signaling pathway and response by resetting tumor-associated macrophages toward the M1 phenotype.
Vicious LQT induced by a combination of factors different from hERG inhibition
Authors: Xu Xinping , Yin Yue , Li Dayan , Yao Binwei , Zhao Li , Wang Haoyu , Wang Hui , Dong Ji , Zhang Jing , Peng Ruiyun 
Published: July 2022

Clinically, drug-induced torsades de pointes (TdP) are rare events, whereas the reduction of the human ether-à-go-go-related gene (hERG) current is common. In this study, we aimed to explore the specific factors that contribute to the deterioration of hERG inhibition into malignant ventricular arrhythmias. Cisapride, a drug removed from the market because it caused long QT (LQT) syndrome and torsade de pointes (TdP), was used to induce hERG inhibition. The effects of cisapride on the hERG current were evaluated using a whole-cell patch clamp. Based on the dose-response curve of cisapride, models of its effects at different doses (10, 100, and 1,000 nM) on guinea pig heart in vitro were established. The effects of cisapride on electrocardiogram (ECG) signals and QT interval changes in the guinea pigs were then comprehensively evaluated by multi-channel electrical mapping and high-resolution fluorescence mapping, and changes in the action potential were simultaneously detected. Cisapride dose-dependently inhibited the hERG current with a half inhibitory concentration (IC50) of 32.63 ± 3.71 nM. The complete hERG suppression by a high dose of cisapride (1,000 nM) prolonged the action potential duration (APD), but not early after depolarizations (EADs) and TdP occurred. With 1 μM cisapride and lower Mg2+/K+, the APD exhibited triangulation, dispersion, and instability. VT was induced in two of 12 guinea pig hearts. Furthermore, the combined administration of isoproterenol was not therapeutic and increased susceptibility to ventricular fibrillation (VF) development. hERG inhibition alone led to QT and ERP prolongation and exerted an anti-arrhythmic effect. However, after the combination with low concentrations of magnesium and potassium, the prolonged action potential became unstable, triangular, and dispersed, and VT was easy to induce. The combination of catecholamines shortened the APD, but triangulation and dispersion still existed. At this time, VF was easily induced and sustained.
Detecting drug-drug interactions between therapies for COVID-19 and concomitant medications through the FDA adverse event reporting system
Authors: Jeong Eugene , Nelson Scott D. , Su Yu , Malin Bradley , Li Lang , Chen You 
Published: July 2022

Background: COVID-19 patients with underlying medical conditions are vulnerable to drug-drug interactions (DDI) due to the use of multiple medications. We conducted a discovery-driven data analysis to identify potential DDIs and associated adverse events (AEs) in COVID-19 patients from the FDA Adverse Event Reporting System (FAERS), a source of post-market drug safety.Materials and Methods: We investigated 18,589 COVID-19 AEs reported in the FAERS database between 2020 and 2021. We applied multivariate logistic regression to account for potential confounding factors, including age, gender, and the number of unique drug exposures. The significance of the DDIs was determined using both additive and multiplicative measures of interaction. We compared our findings with the Liverpool database and conducted a Monte Carlo simulation to validate the identified DDIs.Results: Out of 11,337 COVID-19 drug-Co-medication-AE combinations investigated, our methods identified 424 signals statistically significant, covering 176 drug-drug pairs, composed of 13 COVID-19 drugs and 60 co-medications. Out of the 176 drug-drug pairs, 20 were found to exist in the Liverpool database. The empirical p-value obtained based on 1,000 Monte Carlo simulations was less than 0.001. Remdesivir was discovered to interact with the largest number of concomitant drugs (41). Hydroxychloroquine was detected to be associated with most AEs (39). Furthermore, we identified 323 gender- and 254 age-specific DDI signals.Conclusion: The results, particularly those not found in the Liverpool database, suggest a subsequent need for further pharmacoepidemiology and/or pharmacology studies.
Metabonomic analysis of abnormal sphingolipid metabolism in rheumatoid arthritis synovial fibroblasts in hypoxia microenvironment and intervention of geniposide
Authors: Ke Jiang-Tao , Zhang Heng , Bu Yan-Hong , Gan Pei-Rong , Chen Fang-Yuan , Dong Xin-Tong , Wang Yan , Wu Hong 
Published: July 2022

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a joint hypoxia microenvironment. Our previous untargeted metabolomics study found that sphingolipid (SPL) metabolism was abnormal in the joint synovial fluid samples from adjuvant arthritis (AA) rats. Geniposide (GE), an iridoid glycoside component of the dried fruit of Gardenia jasminoides Ellis, is commonly used for RA treatment in many Asian countries. At present, the mechanism of GE in the treatment of RA, especially in the joint hypoxia microenvironment, is not entirely clear from the perspective of SPL metabolism. The purpose of this research was to explore the potential mechanism of abnormal SPL metabolism in RA joint hypoxia microenvironment and the intervention effect of GE, through the untargeted metabolic analysis based on the ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Arthritis index, foot swelling and histopathology were used to assess whether the AA rat model was successfully established. The SPLs extracts collected from AA rats’ synovial tissue, serum and rheumatoid arthritis synovial fibroblasts (RASFs, MH7A cells, hypoxia/normoxia culture) were analyzed by metabolomics and lipdomics approach based on UPLC-Q-TOF/MS, to identify potential biomarkers associated with disorders of GE regulated RA sphingolipid metabolism. As a result, 11 sphingolipid metabolites related to RA were screened and identified. Except for galactosylceramide (d18:1/20:0), GE could recover the change levels of the above 10 sphingolipid biomarkers in varying degrees. Western blotting results showed that the changes in ceramide (Cer) level regulated by GE were related to the down-regulation of acid-sphingomyelinase (A-SMase) expression in synovial tissue of AA rats. To sum up, this research examined the mechanism of GE in the treatment of RA from the perspective of SPL metabolism and provided a new strategy for the screening of biomarkers for clinical diagnosis of RA.
Early Developmental Trajectories in Infants With Neurofibromatosis 1
Authors: Garg Shruti , Wan Ming Wai , Begum-Ali Jannath , Kolesnik-Taylor Anna , Green Jonathan , Johnson Mark H. , Jones Emily 
Published: July 2022

ObjectiveTo examine the trajectories of cognitive, motor and behavioural development in infants with NF1 compared to infants without a family history of neurodevelopmental difficulties.Study designInfants with NF1 and low-risk controls were recruited from 5 months of age and followed longitudinally. Data from standardised tests was gathered at 5, 10 and 14 months and developmental trajectories of motor, language, behaviour, sleep, social development and parent–infant interaction were examined. Linear mixed modelling was used to estimate group differences in cognitive and behavioural measures over time.ResultsNo group differences were observed on Mullen Scale of Early Learning, overall adaptive functioning, temperament or behavioural measures. There were no group differences observed on measures of social communication or parent–infant interaction. Over the course of development, the NF1 group slept less and took more time to settle to sleep as compared to the control group. Maternal education was significantly associated with cognitive and behavioural developmental outcomes in both groups.ConclusionCognitive, social and behavioural impairments are a cause of significant functional morbidity in children with NF1. This report is the first study to investigate the trajectories of cognitive, motor and behavioural development in infancy in NF1. Our results demonstrate that overall cognitive and behavioural developmental trajectories of the NF1 group in the infancy period are similar to controls. Given previous reports of delayed development in the NF1 cohort by 40 months, early clinical interventions strategies to promote sleep hygiene may be beneficial to optimise developmental outcomes.
Intramuscular ketamine vs. escitalopram and aripiprazole in acute and maintenance treatment of patients with treatment-resistant depression: A randomized double-blind clinical trial
Authors: Cigognini Marco Aurélio , Guirado Alia Garrudo , Meene Denise van de , Schneider Mônica Andréia , Salomon Mônica Sarah , Alexandria Vinicius Santana de , Adriano Juliana Pisseta , Thaler Ana Maria , Fernandes Fernando dos Santos , Carneiro Adriana , Moreno Ricardo Alberto 
Published: July 2022

ObjectiveKetamine, an N-methyl D-aspartate (NMDA) receptor antagonist, can promote rapid action in the management of individuals with treatment-resistant depression (TRD) at sub-anesthetic doses. However, few studies have investigated the long-term use of ketamine administered intravenously (IV) and intranasally (IN). We report the design and rationale of a therapeutic trial for assessing the efficacy, safety, and tolerability of repeated-dose intramuscular (IM) ketamine vs. active treatment (escitalopram and aripiprazole) in TRD patients.MethodsA comparative, parallel-group, randomized double-blind trial assessing the efficacy, safety, and tolerability of acute (4 weeks) and maintenance (24 weeks) use of IM ketamine (0.75 mg/kg) vs. active control (escitalopram 15 mg and aripiprazole 5 mg) in individuals with moderate-severe intensity TRD (no psychotic symptoms) with or without suicide risk will be conducted. Patients with TRD (18–40 years) will be randomized and blinded to receive ketamine IM or active treatment at a 1:1 ratio for 4 weeks (active treatment) and 24 weeks (maintenance treatment). Subjects will be assessed using clinical scales, monitored for vital signs (VS) after application of injectable medication, and undergo neuropsychological tests. The primary outcome will be changed on the Montgomery-Åsberg Depression Rating Scale (MADRS) during the course of the trial. The study is in running.ResultsThis study can potentially yield evidence on the use of IM ketamine in the treatment of depressive disorders as an ultra-rapid low-cost therapy associated with less patient discomfort and reduced use of medical resources, and can elucidate long-term effects on different outcomes, such as neuropsychological aspects.ConclusionsThe trial can help promote the introduction of a novel accessible approach for the treatment of complex disease (TRD) and also allow refinement of its long-term use.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04234776, identifier: NCT04234776.
Prospective Associations of Lifetime Post-traumatic Stress Disorder and Birth-Related Traumatization With Maternal and Infant Outcomes
Authors: Martini Julia , Asselmann Eva , Weidner Kerstin , Knappe Susanne , Rosendahl Jenny , Garthus-Niegel Susan 
Published: July 2022

ObjectiveMany women experience traumatic events already prior to or during pregnancy, and delivery of a child may also be perceived as a traumatic event, especially in women with prior post-traumatic stress disorder (PTSD). Birth-related PTSD might be unique in several ways, and it seems important to distinguish between lifetime PTSD and birth-related traumatization in order to examine specific consequences for mother and child. This post-hoc analysis aims to prospectively examine the relation of both, lifetime PTSD (with/without interpersonal trauma) and birth-related traumatization (with/without postpartum depression) with specific maternal and infant outcomes.MethodsIn the prospective-longitudinal Maternal in Relation to Infants' Development (MARI) study, N = 306 women were repeatedly assessed across the peripartum period. Maternal lifetime PTSD and birth-related traumatization were assessed with the Composite International Diagnostic Interview for women. Maternal health during the peripartum period (incl. birth experience, breastfeeding, anxiety, and depression) and infant outcomes (e.g., gestational age, birth weight, neuropsychological development, and regulatory disorders) were assessed via standardized diagnostic interviews, questionnaires, medical records, and standardized observations.ResultsA history of lifetime PTSD prior to or during pregnancy was reported by 25 women who indicated a less favorable psycho-social situation (lower educational level, less social support, a higher rate of nicotine consumption during pregnancy). Lifetime PTSD was associated with pregnancy-related anxieties, traumatic birth experience, and anxiety and depressive disorders after delivery (and in case of interpersonal trauma additionally associated with infant feeding disorder). Compared to the reference group, women with birth-related traumatization (N = 35) indicated numerous adverse maternal and infant outcomes (e.g., child-related fears, sexual problems, impaired bonding). Birth-related traumatization and postpartum depression was additionally associated with infant feeding and sleeping problems.ConclusionFindings suggest that both lifetime PTSD and birth-related traumatization are important for maternal and infant health outcomes across the peripartum period. Larger prospective studies are warranted.ImplicationsWomen with lifetime PTSD and/or birth related traumatization should be closely monitored and supported. They may benefit from early targeted interventions to prevent traumatic birth experience, an escalation of psychopathology during the peripartum period, and adverse infant outcomes, which in turn may prevent transgenerational transmission of trauma in the long term.
The association between heightened ADHD symptoms and cytokine and fatty acid concentrations during pregnancy
Authors: Gustafsson Hanna C. , Dunn Geoffrey A. , Mitchell A. J. , Holton Kathleen F. , Loftis Jennifer M. , Nigg Joel T. , Sullivan Elinor L. 
Published: July 2022

ObjectivePrevious research conducted with samples of children suggest that individuals with attention-deficit/hyperactivity disorder (ADHD) have altered fatty acid concentrations and may have increased systemic inflammation. Whether these differences are also apparent in other populations of individuals with heightened ADHD symptoms (e.g., pregnant adults) is unknown. The goal of the current study was to examine whether there are ADHD-associated differences in polyunsaturated fatty acid concentrations or pro-inflammatory cytokine concentrations during pregnancy, a developmental period when fatty acid concentrations and systemic inflammation have implications for the health of both the pregnant person and the developing child. We hypothesized that plasma levels of the ratio of omega-6s to omega-3s (n-6:n-3) and plasma inflammatory cytokine levels would be higher in individuals with heightened ADHD symptoms, consistent with previous findings in children with ADHD.MethodsData (N = 68) came from a prospective study of pregnant community volunteers who were oversampled for ADHD symptoms. During the 3rd trimester, plasma concentrations of fatty acids and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were assessed. Dietary intake was examined in the 3rd trimester using three 24-h recalls conducted by trained dietitians and by examining plasma levels of conjugated linoleic acid (n-6) and α-linolenic acid (n-3), essential fatty acids that must come from dietary intake.ResultsThe group with heightened ADHD symptoms had higher n-6:n-3s (β = 0.30, p &lt; 0.01) and higher TNF-α concentrations (β = 0.35, p &lt; 0.001) relative to controls. There were no group differences in dietary variables, as assessed by self-report and via plasma concentrations of essential fatty acids. IL-6 was not reliably associated with ADHD status in this sample.ConclusionPregnant individuals with ADHD, on average, had higher plasma n-6:n-3s and higher TNF-α concentrations relative to controls. A difference was not detected in their dietary intake of fatty acids or other relevant nutrients. Though these null findings are inconclusive, they are consistent with the hypothesis that ADHD-associated differences in plasma fatty acid concentrations are the result of ADHD-associated differences in fatty acid metabolism, rather than simply differences in dietary intake.