dataesr/scientific-paragraphs-categorization huggingface dataset:
Strikingly, our results obtained in the open field and the rotarod tests were in agreement with data obtained by Dalenogare et al. (20). Finally, weak impairments of fine motor coordination were observed only using the grid test, which enabled us to demonstrate and quantify this symptom in QuilA-EAE mice. The grid test is known to highlight subtle ataxic behaviors in mice, often related to cerebellar dysfunctions  (54).
Evaluation of Anxiety-Related Behaviors in QuilA-EAE Mice Anxiety disorders are found in 37. 5% of MS patients  (55). Until now, anxiety-like behaviors were only described in the CFA EAE mouse model. These experimentations showed a reduced exploratory behavior using the light/dark box test  (56, 57) , the elevated plus maze  (58) , and open field test  (56, 58). In all these studies, behavioral experiments were performed during the pre-symptomatic phase of the disease before the appearance of motor defects. To our knowledge, we are the first to evaluate these behaviors in an QuilA-EAE model. Our data using the elevated plus maze, marble burying, and the open field test showed no anxiety-related behaviors in QuilA-EAE mice. The discrepancy between our results and those already described in the literature might be due to the difference between CFA and QuilA-EAE models or the difference in the timing of the behavioral evaluation (presymptomatic vs.
In line with the literature, the data obtained in our study confirmed that if cognition defects do occur in QuilA-EAE mice, then they are slight. In fact, in only one cohort did we find a decrease in social recognition using the social preference and social novelty test. None of the other cognitive functions evaluated (working and episodic memories, anxiety-related behaviors) were affected. The very limited occurrence of anxiety-related behaviors or cognitive dysfunctions in our study can be seen as a limitation of the QuilA-EAE model. However, before drawing conclusions, some aspects have to be taken into account. First, in our study, interfering symptoms were evaluated only at D30. It is thus still possible that some symptoms could arise earlier or later in the disease time course. Secondly, we did not evaluate depressionlike behaviors in our model.
Finally, we show that QuilA-EAE mice could be susceptible to social memory defects but did not exhibit episodic or working memory defects or anxiety-related behaviors. All these data confirm that this QuilA-EAE model represents a useful new model of MS. It now needs further neuropathological characterization before it can be used to identify new therapeutic agents dedicated to sensitive defects in MS. connected to a PowerLab 26T USB data acquisition device (ADInstruments Ltd. , Paris, France) coupled to the Labchart 7 (ADInstruments Ltd, Paris, France). To register the air puff exerted by each stimulation, a square card measuring 2. 6 cm 2 was fixed on the force transducer. Air puffs were recorded in a range of 1 mV, low pass 50 Hz, with a trigger fixed at 2 µV. Response to stimulation was recorded for 100 ms before and 1 s after, with a sample rate of 10 kHz.
For each stimulation (1-3), 60 air puffs were applied to the card and data recorded with Labchart. To determine the characteristic of the stimulations (1-3), the curves illustrating air puff variations in volts were analyzed using the Labchart to measure peak duration (s) and max intensity (µV). Graphical representations were obtained after data were extracted with MATLAB (MathWorks, Natick, USA) and mean confidence intervals for each stimulation were calculated and converted to pounds per square inch (psi). Supplementary Figure  S2  | Pharmacological evaluation of pregabalin effects on locomotor activity using the open-field test in wild-type (WT) female mice. Evaluation of spontaneous locomotor activity using the open-field test. Locomotion was evaluated using the total distance traveled ± SEM for the overall 120 min session.
FUNDING This work was supported by the  Ministère français de l'Enseignement supérieur et de la Recherche  (AD Ph. D. fellowship) and  French government IDEX-ISITE initiative  (grant number  16-IDEX-0001-CAP 20-25 ) of the  University of Clermont Auvergne. It was specifically funded by grants from  ARSEP Foundation  ( AAP 2014 ).
Data collection, definition of terms, and analysis Data extracted from patient's records included age, sex, history of addiction or disease, type of illicit substance and number of packets, clinical presentations, radiographic finding(s), and follow-up data. Patients were classified as asymptomatic or symptomatic. Symptomatic forms were divided into simple and severe forms. A severe symptomatic form was defined by the failure of 1 or more organs related to cocaine intoxication including seizures, hemorrhagic and ischemic strokes, myocardial infarction, aortic dissection, rhabdomyolysis, mesenteric ischemia, acute renal injury and multiple organ failure or mechanical complication of the pellets, such as intestinal obstruction. 5 Cocaine poisoning was defined by the presence of clinical signs that could not be explained by the arrest alone (stress, anxiety) AND by the presence of known clinical signs of cocaine poisoning AND by the presence of a positive urine test for cocaine (look for metabolite benzoylecgonine).
Evolution, management, and hospitalization data All patients received treatment with oral osmotic laxative (∼ 4 liters of polyethylene glycol per 24 hours), unless patients refused (n = 11, 4. 0%) or had already eliminated pellets. Hospitalization allowed the monitoring of patients during the pellet evacuation period. The patients were monitored for 2 types of complications: the risk of rupture, therefore of cocaine intoxication, and the risk of occlusion because of the lack of evacuation. Of the 9 patients presenting with cocaine poisoning symptoms, no treatment was required. However, 10 digestive endoscopies were carried out because of pellet evacuation delays, but there were no complications. The pellets could not be completely removed in 2 cases and were eliminated naturally later after the procedure.
Methods: The IQVIA Longitudinal Prescription databases were used. Risk factors of treatment discontinuation were identified by a multilevel survival regression using Cox proportional hazards model. Kaplan Meier analyses were performed by identified significant risk factors. Results: Twenty-five thousand three hundred sixty-one patients (France: 9,720; Germany: 14,461; Belgium: 1,180) were included. Over a one-year follow-up period, a significant lower treatment discontinuation was observed for patients newly initiated on paliperidone palmitate (53. 8%) than those on risperidone microspheres (85. 4%). Additionally, a significantly lower treatment discontinuation was found for 'stable' PP3M patients (19. 2%) than 'stable' PP1M patients (37. 1%). Patients were more likely to discontinue when drugs were prescribed by GP only (HR = 1.
Long-acting antipsychotic treatment (LAT) offers an important alternative to oral APs in the context of medication continuation. Several antipsychotics, such as risperidone, olanzapine, paliperidone palmitate, and aripiprazole, are approved in Europe in both oral and LAT preparations. Reported treatment continuation differ markedly depending on the study design  [11]. In randomized controlled trials (RCT) or prospective observational studies, adherence is optimized by protocol and is a major driver of treatment continuation  [12]. Therefore, a retrospective design is recommended when studying questions related to effectiveness, as looking back to what already happened is by its nature noninterventional  [13, 14]. Moreover, by using nationwide electronic databases, a large number of patients can be included in retrospective observational studies to achieve enough statistical power and facilitate the generalization of findings  [15].
Data sources Data were extracted from the IQVIA Longitudinal Prescription databases (LRx) for France, Germany and Belgium and have covered approximately 33%, 60% and 25% respectively of all retail pharmacies. The three countries have been selected as data were collected in a similar way. Moreover, the three countries are among the countries with the highest number of patients initiated on PP3M as of its commercial availability in Europe. The databases contain actual prescription pickup data from pharmacy records for anonymized patients. Only pharmaceutical products purchased in retail pharmacies are recorded and no data from the hospital pharmacies are captured. Data from retail pharmacies were further de-identified by a Trusted Third Party before transferring to IQVIA. Key patient information includes prescribed and dispensed drug, molecule, brand and generic name, manufacturer, form, strength, dose, pack size, method of administration, quantity, and prescription dispensing date.
Other data include gender, physician specialty, concomitant medication, cost of prescriptions, and health insurance status. Age was available in the German and French but not the Belgian database. Information on patients' diagnosis and disease severity was not available. These databases have been used by IQVIA to study questions of persistence in schizophrenia  [19]  as well as in other psychiatric  [21]  and persistence topics  [22, 23]. A unique patient identifier was used to ensure patients visiting different pharmacies within the panel were followed in all the three countries. Only data from pharmacies which transmitted data every month were used. Ethical approval was not required for this research as only deidentified/anonymized electronic databases were used. It was therefore not necessary to acquire any administrative permissions and/or licenses to access clinical/personal data used in this research.
Moreover, as treatment continuation with PP1M was impacted artificially following the availability of PP3M-as patients may discontinue PP1M simply to switch to PP3M-patients on PP1M prior to the availability of PP3M were selected. Patient inclusion criteria were: (1) had at least one transaction of any drug during six months prior to initiation of the study drugs; (2) had at least two transactions of any drug on two distinct dates during the 12 months after initiation; (3) 18 years old and above at index date as the study drugs were not indicated for patients younger than 18 years. Age was not available in the Belgian database, thus this inclusion criteria was not applied; (4) patients with no missing or unknown values of studying variables, except for patients with missing values of age in Belgium;  (5)  patients not purchasing two or more LATs concomitantly.
It was calculated as such so that if a patient purchases oneunit drug from pharmacies not included in the databases, the patient would still be considered on continuous treatment. The administration window of risperidone microspheres was not mentioned in the SmPC and was set as half of that of PP1M. A sensitivity analysis was conducted across products, applying an equal grace period of 120 days (proxy to the longest grace period in the base case). The coverage and grace period lengths were summarized in Table  1.
Data extracted Of the selected patients, data about gender, any product purchased between six months before and three months after the index date, date of transactions, dosage, and specialty of the prescribers of the study drugs were extracted from the three databases and pooled together. Age was extracted from the French and German databases only, as it was not available in Belgium. Previous treatments, i. e. products purchased six months before the index date were classified as index drug; other  (1)  [coverage period of 1 unit]×[number of units in the last purchase]+[grace period] (2) [Time between initiation and last purchase before treatment stop] +[coverage period of 1unit] × [number of units in the last purchase] LATs; oral APs; and no AP. Patients with no purchase of other APs during the first three months after index, except for oral risperidone or oral paliperidone, were referred as patients on monotherapy.
Discussion This study shows that patients newly initiated on paliperidone palmitate had a significantly higher treatment continuation compared to those on risperidone microspheres based on national, longitudinal, prescription databases of retail pharmacies in France, Germany and Belgium. Receiving drugs prescribed by GP only, being previously treated with oral AP or no treatment, and receiving combination therapy were risk factors for treatment discontinuation. On the other hand, older patients and patients receiving relatively high dose of treatment were less likely to discontinue treatment. Additionally, stable PP3M patients had a significantly higher treatment continuation than stable PP1M patients. Results from our study are in line with previous publications that patients on paliperidone palmitate have a higher treatment continuation than patients on risperidone microspheres  [19, 20, 24].
Typically, retrospective studies demonstrate lower treatment continuation than prospective studies, because, although non-interventional, there is still the sense of the controlled trial environment, including the contact with study centres. Additionally, methodological elements influence the results. All prescription interruptions longer than the permissible gap were considered as treatment discontinuations, irrespective of reasons for the discontinuation. It is possible that in some cases the treatment is not discontinued, but the patient is, for example, hospitalized. While the above limitations are a consequence of the databases used, methodological parameters like the length of the grace period have important consequences as well. The impact of the grace period was evaluated in a sensitivity analysis using more pragmatic and longer periods.
It is possible that positive symptoms of patients on a low dose of treatment were not sufficiently improved. Furthermore, patients on a higher dose Fig. 2  Overall and by product treatment discontinuation (total sample) -patients newly initiated on paliperidone palmitate and risperidone microspheres of treatment are likely to have a more severe form of disease and thus receive more professional and family support than those whose disease is mild. However, as data about disease severity is not available in the LRx databases, it is not possible to confirm this hypothesis. Similarly, patients on a combination therapy are more likely to experience medication-related adverse events and thus discontinue. In our study, patients on a combination therapy are 5% more likely to discontinue than patients on monotherapy.
Psychiatrist and GP have complementary skills and that collaboration between GP and psychiatrist should be encouraged  [37, 38]. Thus, managing patients by a multi-disciplinary team could be an effective intervention to improve treatment continuation in schizophrenia patients. Several limitations in this study should be noted. First, the analyses performed using the LRx databases are retrospective and do not provide substantial information on patients' clinical and functional outcomes that could be associated with treatment discontinuation. Such limitation is common to retrospective observational studies using routinely collected electronic data platforms (not designed for specific research investigations). Therefore, no conclusions can be drawn concerning possible underlying confounders such as severity of disease, prevalent complications or other individual circumstances.
| Highly sensitized dialysis controls A group of 10 waitlisted highly sensitized patients on hemodialysis, followed at Grenoble University Hospital, was included for analysis as a control, to reflect potential differences between healthy donors and Chronic Kidney Disease (CKD) patients. This group was referred to as CKD and did not receive tocilizumab. All patients gave their written and informed consent for the analysis of the generated data (CNIL [French National committee for data protection] approval number 1987785v0).
Plasmablasts were identified as CD19 + CD27 + CD38 high IgD - cells, whereas CD19 low CD38 high IgD -identified plasma cells. Memory B cells were identified as CD19 + CD27 + CD38 -IgD +. Cell debris and doublets were excluded based on side-versus-forward scatter, and dead cells were excluded using Fixable Viability Dye (FVD) eFluorTM 506 (eBiosciences). Cells were analyzed on a FACS CANTO II cytometer using FACS Diva (BD Biosciences) software.
| HLA antibody testing Sera were tested using the SA Luminex standard detection technique (Immucor® [Belgium]). The retained MFI values corresponded to the manufacturer's Background Corrected MFI (BCM) value. Results were processed using Match It® and Fusion® software. Positivity for the SA Luminex analysis was defined as an MFI >1000. For some patients, in whom we suspected that there was a prozone effect in their serum, sera were diluted at 1/5th to 1/20th. A systematic serial dilution analysis was not performed, but this targeted dilution analysis allows to detect and limit the impact of the prozone effect. The detailed analysis of HLA antibodies is presented in our associated work focusing on the same patients' cohort. 21 lo-reactive antibodies were detected using SA Luminex technology.
Calculation of CD4 T-Cell Count Change For ECs enrolled in the CIHR/CTN 247 study, sequential CD4 T-cell counts were prospectively combined with historical data from medical charts for each study participant. The rate of CD4 T-cell count change over time was computed using a linear regression analysis. The results were reported as annual changes in CD4 T-cell counts. The annual slope of CD4 T-cell count change was assessed for significant difference from "0"  [29].
Statistical Analyses GraphPad Prism 9. 3. 0 (GraphPad, La Jolla, CA, USA) and SPSS 24. 0 (IBM SPSS, Chicago, IL, USA) were used for statistical analyses. The statistical significance of differences between groups was assessed using nonparametric Kruskal-Wallis' tests with Dunn's post-tests. A Spearman's rank test was used to assess correlations. An α level of 5% was considered statistically significant (p-value). Multivariable linear regression analyses were performed using SPSS 24. 0.
L. R. is a post-doctoral fellow supported by the "Fonds de perfectionnement" of the Geneva University Hospitals, Switzerland, and the Swiss National Science Foundation. S. I. is a post-doctoral fellow supported by the FRQ-S and CIHR/CTN. The Canadian HIV and Aging Cohort Study is supported by operating grants TCO-125276 and HAL-157985 from the Canadian Institutes of Health Research, and receives support from the CIHR HIV Clinical Trial Network (project CTN 272. ) MD is supported by a clinician-researcher salary award from the Fonds de recherche du Québec-Santé CT is the Pfizer/Université de Montral Chair on HIV translational research. G. K. is supported by the Ligue Contre le Cancer (équipe labellisée); the Agence National de la Recherche (ANR); the Institut National du Cancer (INCa); the Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); and the Seerave foundation.
This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. J. -P. R is the holder of the Louis Lowenstein Chair in Hematology and Oncology, McGill University. Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the McGill University Health Centre (studies 2019-5170, 2013-2134) and the Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) (studies 2013-2134, MP-02-2012-3068 and CE 11. 063-BSP).
Data were analyzed by the Axio Vision software (vs 4. 8). Ex Vivo Characterization of NPs in Ussing Chambers with Human Jejunal Tissue. Human Jejunal Tissues. Samples of jejunum were collected from morbidly obese subjects undergoing Roux-en-Y gastric bypass surgery at the Uppsala University Hospital, Uppsala, and the Vrinnevi hospital, Norrkoping, Sweden. Subjects followed a low-calorie diet for 3 weeks prior to surgery and did not suffer from inflammatory or infectious bowel diseases at the time of surgery. Subjects diagnosed with type I or II diabetes were excluded from the study. Samples were taken 60 cm from the ligament of Treitz. The study was reviewed and approved by the regional ethical review boards of Uppsala (Approval DNR 2014/531, approval date 2015-03-18) and Linkoping (Approval DNR 2013/472-31, Addendum 2015/44-32, approval date 2015-11-20), Sweden.
Tissues were pretreated with the dynamin inhibitor dynasore (Sigma-Aldrich) at 80 μM for 15 min before addition of NP. As a control for endocytosis, a 3 kDa lysine-fixable fluorescently labeled dextran (FD3, ThermoFisher) was used. Inhibition of transcytotic permeability was tested using horseradish peroxidase (HRP, Sigma-Aldrich). Permeabilities of NP and HRP were measured, and after the experiment, internalization of nanoparticles and FD3 was investigated by microscopy. HRP permeability was analyzed by ELISA as previously described. 36, 62 PLC-MSMS Analysis. Samples containing pharmacological probes were analyzed on an ACQUITY UPLC (Waters) instrument linked to a Xevo triple-quadrupole tandem mass spectrometer (Waters). LC and MS methods were optimized for each compound. Results were quantified using TargetLynx software (Waters).
Insulin Analysis. Permeated insulin was analyzed by HPLC-MSMS. LC (Shimadzu HPLC system LC 20AD, Japan) with a 150 × 2. 1 mm-5 μm-300 Å HPLC C8 column (Interchim, France) was used for the elution of insulin with a gradient method. Mobile phases A and B were 0. 1% formic acid solution and acetonitrile containing 0. 1% formic acid, respectively. The flow rate was 0. 6 mL/min. 100 μL of the tested sample was treated with 200 μL of chloroform/methanol/ water at 1/1/0. 3 and 100 μL of 0. 1 M NaOH, and then, 40 μL of analyte was injected onto the column placed in an oven at 60 °C. The total run time was 13 min. Tandem mass spectrometry in positive electrospray mode was used for detection. System control and data processing were carried out using MassLynx software version 4. 1. Spray voltage was 3.
5 mg/mL, nuclear stain, ThermoFischer), fluorescently labeled phalloidin (0. 13 μM, actin stain, ThermoFisher), and fluorescently labeled wheat germ agglutinin (4 μg/mL, membrane stain, Thermo-Fisher). Fluorophore labels were selected to not interfere with the fluorescent signal from the labeled NP. Coverslips (High Precision No. 1. 5H, Paul Marienfeld GmbH, Lauda-Konigshofen, Germany) were mounted with Prolong Diamond Antifade mounting medium (ThermoFisher). Images were acquired on a Zeiss Elyra S. 1 SIM instrument in LSM mode and Zeiss BF/LF Axioimager microscopes at the Uppsala university core facility Biovis. Images were deconvoluted using Huygens software and processed using ZEN (Zeiss) and IMAGE J software. Quantitation of cells and NPs was performed using ImageJ. To evaluate NP interaction with tissues, five sections from each of two tissue specimens from two parallel Ussing chambers were stained, imaged, and analyzed.
ACKNOWLEDGMENTS The authors want to thank  M. Tinnerfelt Wiberg ,  M. Wiren , and  J. D. Söderholm  of  Linköping University, Sweden , for their kind and generous help with Ussing chamber studies. We thank  D. Basile  at  Sanofi Pharma  for help with insulin glulisine analysis in in situ experiment samples. The work was supported by the  European TRANS-INT  Consortium, which received funding from the  European Union 's  Seventh Framework Programme  for research, technological development and demonstration under grant agreement  281035. P. L. , G. K. , Z. N. , L. N. T. , F. M. , I. S. , A. B. , A. M. , N. C. , V. P. , D. J. B. , M. J. A. , and P. A. received funding from  TRANS-INT  for this study. P. A. was also supported by the  Swedish Research Council  (grant approval  2822  and  2020-01586 ).