dataesr/scientific-paragraphs-categorization huggingface dataset:
French pharmacovigilance data During the study period, 829,761 spontaneous ADR reports were registered in the FPVD, 2,120 were psoriatic conditions of which 94 occurred with CCBs. The mean age of patients was 68 ± 11 years (range 34 -93 years), the male/female ratio was 3. 4 (72 men and 21 women). Thirty four reports (36%) were considered serious; the seriousness criteria were "hospitalization or prolongation of existing hospitalization" (n = 20) and "other serious medical situations" (n = 14). The indications for CCB use, where completed (n = 54), were hypertension (n = 48), angina pectoris (n = 2), arrhythmia (n = 1), ischaemic cardiomyopathy (n = 1), facial neuralgia (n = 1) and ischaemic heart disease prophylaxis (n = 1). Sixty five percent of reports (n = 61) were coded as "psoriasis" (without further detail), 34% as "psoriasiform dermatitis" (n = 32), one case as "erythrodermic psoriasis".
Time to onset ranged from 4 months to 143 months, with an average of 38. 4 months. Time to onset was less than 2 years in 50% of cases. The OR was 3. 5 (95%CI 1. 3 -16. 6). The authors suggested that a further large population study was needed to conclude on this possible association  [15]. In another case-control study, conducted between 1994 and 2005 on the UK general practice research database, 36,702 cases with a first-time psoriasis diagnosis and 36,702 matched controls were included; 3202 cases were on CCBs. In this publication, the findings of Brauchli et al. did not support the hypothesis that CCB use was associated with an increased risk of psoriasis (OR 0. 97, 95% CI 0. 88 -1. 07)  [16]. Finally, in a prospective cohort study using the Nurses' Health Study data, conducted from June 1996 to June 2008, 843 incident psoriasis cases among 77,728 participants were documented; 96 cases had taken CCBs.
[14] , are congruent. Almost all CCBs were involved, DHPs as well as non-DHPs, suggesting a class effect. The time to onset was generally less than 2 years, and outcome was favorable after drug discontinuation. Typical psoriatic lesions as well as psoriasiform lesions were described. Psoriasiform lesions differ from typical psoriatic lesions in terms of size, shape and anatomical distribution  [31]. Both induction and exacerbation cases were observed. Data from epidemiological studies regarding the association between CCB use and psoriasis risk are conflicting. Only one study highlighted a significant association. This study included first diagnoses as well exacerbation cases, but was limited by its small size  [15]. No association was found between CCBs and psoriasis in the studies conducted using the UK general practice research database and the nurses' health study data; even after long exposure  [16, 17].
Conclusion This case/non-case study using data from the French national Pharmacovigilance database highlights a statistically significant association between the risk of psoriasis, and CCB exposure, which constitutes a potential safety signal. This risk is a class effect, time to onset is generally less than 2 years, and outcome is favorable after drug discontinuation. Both onset and exacerbation, and both typical psoriatic eruptions and psoriasiform eruptions are involved. A critical gap exists in identifying the causes of psoriasis flares, especially the potential role of drugs. Health authorities should sensitize healthcare workers to the risk of psoriasis with CCBs. Particular attention should be paid to patients taking CCB and ACEI concomitantly. Given the suggestive reports in the FPVD and in the literature, the SmPC of all CCBs should mention this risk.
On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.
11 The increasing use of remdesivir during the COVID-19 pandemic has created an urgent need to elucidate its safety profile, particularly for CV AEs that are often infrequent but lethal to patients with COVID-19. Therefore, we conducted a large observational pharmacovigilance study using the World Health Organization (WHO) global database of individual case safety reports (ICSRs),  12  to detect CV signals with high resolution and characterize the CV AEs of remdesivir. [15] [16].
Study design and data source This large retrospective pharmacovigilance cohort study was conducted using data from VigiBase, the WHO global deduplicated ICSR database,  12  which contains records from greater than 130 countries and 20 million individuals, until September 1, 2020. Relevant adverse drug reaction (ADR) reports from across the globe have been collected to the database since 1967 as per the WHO Program for International Drug Monitoring (MDR), and is managed by the Uppsala Monitoring Center (UMC, Sweden). The data casemix was separated into case and non-case groups based on the target drug of interest (remdesivir), which were then used for the disproportionality analysis. VigiBase accepts reports from various credible sources, including healthcare workers, patients, and pharmaceutical companies, and the sources are generally provided with postmarketing notifications.
Statistical analysis As VigiBase incorporates a dataset comprising a large sample size collected worldwide, it provides a good fit for the study of disproportionality (also known as case-noncase analysis), for which sufficient sample size is indispensable to warrant applicable power and resolution. 20 e used the analysis to determine whether the proportion of CV toxicities reported for remdesivir differs from that occurring in the drug control group (full database). When patients exposed to a particular medication (cases) have a higher percentage of ADRs than those not exposed to that drug (non-cases), the link between the adverse reaction and the individual active drug may suggest a possible safety concern. Information component (IC) and reporting odds ratio (ROR) are indicator values used for the disproportionate reporting developed by UMC, where an IC 0.
25 (the lower end of a 95% credible interval) greater than 0 or lower confidence interval (CI) of ROR greater than 1 indicates significant associations of specific ADRs with the drugs. ROR was calculated using the chi-square (χ 2 ) test as per the well-established reporting method of pharmacovigilance studies. 21 When the full database was not used as a comparator and sensitivity analyses were conducted, ROR was reported rather than the IC to express disproportionality. 15 Multivariate odds ratios (ORs) with 95% CIs were calculated using a logistic regression model to consider prespecified variables, such as age, sex, and multiple COVID-19 treatment drugs, including hydroxychloroquine, corticosteroid, lopinavir-ritonavir, and interferon. 22, 23 Dexamethasone, hydrocortisone, prednisolone, and prednisone were included for corticosteroid variable as indicated in study protocol and guideline for COVID-19 treatment.
The following statistical formula was used: where N expected = [N drug × N reaction ]/N total. N expected represents the number of case reports expected for the drug-effect combination, whereas N observed indicates the actual number of case reports for the drug-effect combination. Furthermore, N drug and N reaction specify the number of case reports for the drug irrespective of AEs and for the effect irrespective of drug, respectively. 25, 26 N total correspond to the total number of case reports in the full database. Qualitative variables were described as count (percentage), and continuous variables were expressed as median with interquartile range (IQR). The remdesivir and full database cases were compared using the χ 2 test IC = log 2 ([N observed + 0. 5]∕[N expected + 0. 5]) or Fisher's exact test for qualitative variables and the unpaired Kruskal-Wallis test for continuous variables.
Post hoc power analyses of the comparisons between the remdesivir and full database cases as well as the remdesivir and COVID-19 cases were performed using the Z test of independent proportions. All tests were two-sided, and p value less than 0. 05 was considered significant. All analyses were conducted using IBM statistical package for the social sciences (SPSS) version 25. 0 (SPSS Inc. ) or R software, version 3. 6. 0 (R Foundation for Statistical Computing). Power analyses were performed with G*Power, version 3. 1. 9. 6 (Heinrich-Heine-Universität-Düsseldorf).
CV-ADR signals The number of ADRs reported for remdesivir was 2107 by August 30, 2020, and a total of 22,728,189 all-drug ADRs have been reported since the inception of the database. Because ADRs associated with remdesivir during the outbreak of EBOV was not reported to VigiBase, ADRs related to remdesivir were first recorded in VigiBase in February 2020, after the outbreak of COVID-19. The total number of all-drug ADRs corresponding to the interval of interest (from February 2020 to August 2020) was 1,403,532. The number of specific CV-ADRs is listed in Table  1. The total number of patients with COVID-19 included in our analysis was 5408, and the sensitivity analysis of the COVID-19 population alone is described in Table  2. Median (IQR) drug treatment duration (days) ranged from 0 (0-4) days for ventricular fibrillation to 4 (1-5) days for atrial fibrillation (Table  3 ).
The indication for remdesivir was COVID-19-positive for all reported patients. Post hoc power analysis of the closest proportion comparison (atrioventricular block) revealed a power of 0. 634, with the second closest comparison (myocarditis) revealing a power 0. 996. We identified eight candidates among 37 broad CV outcomes where CV-ADRs were significantly higher in remdesivir than they were in the entire database (non-cases; Table  1 ). Remdesivir was associated with higher reporting of cardiac arrest (ROR: 19. 9, 95% CI: 16. 1-24. 5, IC 0. 25 : 3. 2 ). After further adjustment for various confounders, including corticosteroid use, cardiac arrest (adjusted OR [aOR]: 1. 88, 95% CI: 1. 08-3. 29), bradycardia (aOR: 2. 09, 95% CI: 1. 24-3. 53), and hypotension (aOR: 1. 67, 95% CI: 1. 03-2. 73) were significantly associated with the use of remdesivir.
Cardiotoxicity analyses was performed using hPSC-CMs (hESC-CMs and hiPSC-CMs cell lines) in the presence of various concentrations of remdesivir. After 24 and 48 h posttreatment, cell viability was determined by using the CellTiter 96 AQueous One Solution Cell Proliferation Assay (MTS, Promega). The data represent the mean (±SD) of at least two independent experiments performed in triplicate. CC 50 , 50% cytotoxic concentration; hESC-CMs, cardiomyocyte derived from human embryonic stem cells; hiPSC-CMs, cardiomyocytes derived from human embryonic stem cells outcomes; these were cardiac arrest, bradycardia, shock, hypotension, atrial fibrillation, ventricular tachycardia, ventricular fibrillation, and AMI (Table  1 ). To distinguish drug-induced CV-ADRs from COVID-19-induced CV effects,  18, 19  we further restricted the analysis to patients with COVID-19 and the results were consistent, except for cardiogenic shock, atrial fibrillation, and ventricular tachycardia.
However, the effect sizes (ROR) of all CV-ADRs were smaller than those of the results of the overall population, indicating that the RORs of CV-ADRs derived from the overall database were overestimated, perhaps due to the intrinsic COVID-19 CV deleterious effects (Tables  1  and 2 ). After further adjustment for potential confounders (i. e. , corticosteroid use), cardiac arrest (aOR: 1. 88, 95% CI: 1. 08-3. 29), bradycardia (aOR: 2. 09, 95% CI: 1. 24-3. 53), and hypotension (aOR: 1. 67, 95% CI: 1. 03-2. 73) were significantly associated with the use of remdesivir. The prevalence in the VigiBase for cardiac arrest, bradycardia, and severe hypotension was reported to be as high as 3. 58%, 3. 64%, and 3. 97%, respectively, in patients with COVID-19 taking remdesivir, whereas they were 0. 97%, 1.
Nevertheless, our results from VigiBase would be better to be validated by important pharmacovigilance dababase as FDA AE reporting system. Third, the dosage of remdesivir used for in vitro experiments may differ from that used for treatment. As such, the experimental dosages should be taken simply as inferences of a dose-response relationship and evidence of causality, and not actual therapeutic effect measures. Last, our study did not begin with total exposure data for remdesivir but, rather, relies on disproportionality analyses between ADRs of remdesivir and the total number of ADRs reported to the database. However, the advantage of VigiBase and the methods used in this study (disproportionate analysis) has been well-established through numerous studies  [13] [14] [15] [16] 36  and may provide reliable and sufficient evidence to support potential safety concerns with the increased administration of remdesivir.
Values are n (%) or n/N (%), unless otherwise indicated. Availability of data is mentioned in bold and top rows. A severe ADR was defined as life threatening, causing to persistent or significant disability, or requiring hospitalization (first or prolonged) or when causing death. Abbreviations: ADR, adverse drug reaction; A. fib, atrial fibrillation; AMI, acute myocardial infarction; COVID-19, coronarvirus disease 2019; ICSR, individual case safety report; IQR, interquartile range; min-max, minimum-maximum; V. fib, ventricular fibrillation; VT, ventricular tachycardia. T A B L E 3 (Continued) related to remdesivir using the international pharmacovigilance database (VigiBase), which includes information from over 130 countries and 20 million individuals until September 1, 2020. To the best of our knowledge, this is the first population-based pharmacovigilance study on the CV-ADRs of remdesivir.
In this study, we comparatively analyzed CV-ADRs reported to be associated with remdesivir treatment and those for the entire dataset, and identified eight CV-ADRs candidates that were disproportionately associated with remdesivir among 37 broad CV F I G U R E 1 Overlap between cardiovascular entities. AMI, acute myocardial infarction T A B L E 4 Overlap of cardiac ADR associated with remdesivir.
Information component (IC) and its 95% credibility interval lower end point (IC025) comparing cardiac ADRs associated with remdesivir versus entire database in VigiBase (from inception on November 14, 1967, toAugust 30, 2020). A positive IC 025 value (>0) is the traditional threshold used for statistical signal detection (in bold). For significant signals, ROR and its 95% CI were also calculated using entire database from February 1, 2020, to August 30, 2020, as comparator (contemporary control group for remdesivir, first remdesivir report in February 2020). Abbreviations: ADR, adverse drug reaction; CI, confidence interval; ICSR, individual case safety report; NA, not applicable; ROR, reporting odds ratio. T A B L E 2.
Structural Identification Compound 1 (44 mg) was analyzed by IR, mass spectrometry, and NMR (1D and 2D). The IR spectrum showed the presence of hydroxyl (3466 cm -1 ) and carbonyl (1716 cm -1 ) groups (see experimental section and Supplementary Materials for the IR spectrum). The compound was assigned the molecular weight and molecular formula of 351 g/mol and C18H25NO6, respectively, as determined by HRMS (see Supplementary Materials). The 13 C NMR showed 2 carbonyls (176. 1 and 170. 5 ppm), 4 olefinic carbons (133. 6-136. 6 ppm), 4 saturated carbons linked to oxygen (68. 2-82. 5 ppm), and two methyl groups (12. 4 and 14. 3 ppm) ( 13 C NMR data are provided in the experimental section and in Supplementary Materials). The 1 H NMR data were in agreement with the information obtained from the 13 C NMR spectrum and showed a profile similar to those of pyrrolizidine-alkaloids ( 1 H NMR data are provided in the experimental section and in Supplementary Materials).
Structural Identification Compound 1 (44 mg) was analyzed by IR, mass spectrometry, and NMR (1D and 2D). The IR spectrum showed the presence of hydroxyl (3466 cm -1 ) and carbonyl (1716 cm -1 ) groups (see experimental section and Supplementary Materials for the IR spectrum). The compound was assigned the molecular weight and molecular formula of 351 g/mol and C 18 H 25 NO 6 , respectively, as determined by HRMS (see Supplementary Materials). The 13 C NMR showed 2 carbonyls (176. 1 and 170. 5 ppm), 4 olefinic carbons (133. 6-136. 6 ppm), 4 saturated carbons linked to oxygen (68. 2-82. 5 ppm), and two methyl groups (12. 4 and 14. 3 ppm) ( 13 C NMR data are provided in the experimental section and in Supplementary Materials). The 1 H NMR data were in agreement with the information obtained from the 13 C NMR spectrum and showed a profile similar to those of pyrrolizidine-alkaloids ( 1 H NMR data are provided in the experimental section and in Supplementary Materials).
Gene Localization and Related Diseases Human CCK2R was cloned for the first time in 1993  [14]. Cck2r, the gene coding for CCK2R, which is located on the terminal short arm of chromosomes 11 in humans (11p15. 4), is 12 kbp in length and is composed of 5 exons. According to the Ensembl database, three transcripts have been identified in humans. CCK2R splice variants and mutations have been shown to be involved in cell proliferation and cancer pathogenesis  [15]. Mutations, as well as overexpression of CCK2R, are associated with carcinogenesis via the modulation of processes including cell proliferation and cell adhesion.
This database detected CCK2R mRNA in most parts of the human brain, except the thalamus. Some of the structures that express CCK2R are directly implicated in the modulation of pain, such as the hypothalamus, the basal ganglia and the amygdala. The hypothalamus has a role in modulating the affective dimension of pain and is part of the spinothalamic tract, the principal pain tract  [25]  (Figure  1 ). The basal ganglia (mainly including the putamen and the caudate nucleus, and the nucleus accumbens (NAc)) have been principally studied for their motor functions, but are also involved in different aspects of pain including the sensory-discriminative, affective and cognitive dimension of pain and the modulation of nociceptive stimulus intensity information  [26]. The amygdala plays an important role in emotional responses and affective states, in disorders such as learned fear, anxiety and depression, and also in pain modulation  [27].
MTT assays To assess cell viability, MTT reduction assays were performed in accordance with the protocol from Mensah-Nyagan laboratory  (20)  and confirmed preliminary MTT assay readout data generated by the Mensah-Nyagan laboratory. Briefly, SH-SY5Y cells were seeded at 5x10 3 cells/ well into 96-well plate in replicates and allowed to attach. 48 h after the plating, the treatments were initiated. After 24H treatments, cells were incubated with MTT (3-(4,5dimethylthyazol-2-yl)-2,5-diphenyl-tetrazolium bromide) in DMEM for 3 hours. MTT is reduced to a violet formazan derivative by mitochondrial enzymatic activity. At the end of the reaction cells were dissolved in a MTT cell lysis buffer (DMSO). MTT absorbance was measured at 550 nm using the multi label plate reader Cytation3 (BioTek). MTT signal detected for the CTRL cells is arbitrary normalized to 100 %.
Determination of oxygen consumption rate (mitochondrial respiration) and extracellular acidification rate (glycolysis): The Seahorse Bioscience (North Billerica, MA, USA) XF24 Analyser was used to perform a simultaneous real-time measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). XF24 cell culture microplates (Seahorse Bioscience) were coated with 0. 1% gelatine and SH-SY5Y cells were plated at a density of 2. 5x10 4  The OCR and ECAR values from the basal respiration state were recorded simultaneously. Data were extracted from the Seahorse XF-24 software, and the bioenergetics profils using the OCR and ECAR values were calculated according to the guideline of the company  (21).
Statistical analysis Data are given as the mean ± SEM. Values were normalized to the untreated control group (=100%). Statistical analyses were done using the Graph Pad Prism software version 5. 02. One-way ANOVA followed by Dunnett's multiple comparison tests versus the control group were used for statistical comparisons of more than two groups. Student unpaired t-test was used for statistical comparisons of two groups. The experimental data are investigated using the GraphPad-Prism program (GraphPad-Prism, San Diego, CA, USA). P values<0. 05 were considered statistically significant.
Characterization of Loaded Films Transmittance data of loaded films were collected using a Shimadzu UV-2101 spectrometer from 300 to 500 nm. Loaded films were sticky enough to adhere themselves to the sample holder and, therefore, air was used as reference. Raman spectroscopy scans and images of the different types of self-assembled microgel films (bare and loaded ones) were obtained with a WITec Confocal Raman microscope model Alpha 300R + y (Ulm, Germany). Dried film samples were slightly wet with triple distilled water to homogenize them and avoid potential background fluorescence. In a typical experiment, surface and in-depth distribution of the different cosmetic active molecules along the films were determined using a frequency-doubled laser at 532 nm of excitation wavelength at an output power of 7 mW and 600 mm grating.
Raman spectra for image compositions were recorded using a 100X Zeiss, EC Epiplan-Neofluar DIC objective (Oberkochen, Germany) with a numeric aperture of 0. 9. Image resolution was set at 1024 × 127 pixels, with a total of 22,500 spectra per image at a scan speed of 20 s per line and an integration time per pixel of 0. 13 s. Characteristic bands at 1203 and 479 cm -1 , 1349 and 1080 cm -1 , and 3072 and 774 cm -1 for benzophenone-4, DBBH and salicylic acid were used for identification, respectively (see Figure  S1 ). Data acquisition was driven by the WITec Control software (Ulm, Germany). For peak identification in mixed films (cargoloaded ones) Raman spectra of controls, that is, bare polymeric films and free cosmetic active molecules were recorded and compared.
A custom image analysis software (ImageJ) was used to analyze the acquired image sequences. Experiments were repeated from 8 to 10 times for each sample. The evaluation of the drying kinetics was carried out using a similar approach with respect to morphology observations. After being deposited on PDMS substrates, single droplets of WPI/NPC suspensions were gently deposited by tweezers in the weighing chamber of an ultra-micro balance (XP2U, Mettler Toledo), whose plate was previously surrounded by zeolites to control the relative humidity to ≈2%. The droplet mass loss (accuracy of 0. 1μg) was measured at the same environmental conditions (T, RH) of droplet profile tests until a constant mass value was kept for 15s (overall drying time, t dry ). Tests were repeated from 8 to 10 times for each sample, showing significant repeatability (absolute deviation around ±0.