dataesr/scientific-paragraphs-categorization huggingface dataset:
Derivation of maternal dietary inflammatory potential score. Maternal dietary inflammatory potential was scored using the energy-adjusted (using density method) Dietary Inflammatory Index (E-DII), a well-validated literature-derived score derived from the Dietary Inflammatory Index (DII) of which development has been described in detail elsewhere  [39]. Briefly, dietary information for each mother was converted to amount per 1,000-kcal values and then linked to a regionally representative database, which provides an overall estimate of mean and standard deviation of energy-standardized intakes for each of the dietary parameters (i. e. , nutrients, foods, and other food components), which also were adjusted for energy using the density method. By subtracting the mean of the energy-adjusted regionally representative database from the participants-reported amount and dividing this value by the parameter's representative standard deviation, z-scores for each dietary parameter were derived.
Covariates Important covariates were identified and harmonized for subsequent analyses. These included maternal height (in cm), prepregnancy body mass index (BMI; in kg/m 2 ), maternal age at delivery (in year), maternal education status (study-specific definition of low/medium/high), self-reported maternal birth place/maternal ethnicity (European-born/white or non-European-born/non-white), maternal cigarette smoking (never/ever/current), maternal alcohol intake during pregnancy (yes/no), maternal parity (primiparous/multiparous), and infant sex (male/female). These data were originally collected by questionnaires (interviewer-or selfadministered) or abstracted from birth records. Data are expressed in different units and categories in different studies, thus we harmonized the covariates across studies through standardizing units and categories for downstream analysis.
Statistical analysis Participants' characteristics were summarized for the ALPHABET consortium and according to its constituent studies. These were limited to participants with availability of the exposure (maternal diet) and main outcomes (birth weight or gestational age) information. We further excluded participants with implausible energy intakes (<500 or >3,500 kcal/d) to avoid extreme misreporting  [47, 48]. A 2-stage individual participant data meta-analysis was used to assess the associations between maternal diet quality and inflammatory potential and birth outcomes. Cohort-specific effect estimates were first obtained by using linear and logistic regressions for continuous and binary outcomes, respectively. The effect estimates were then pooled using random-effects meta-analysis following methods described by DerSimonian and Laird  [49] , which considers both within-and between-study variability.
Chained equation  [52]  was used to impute the missing covariates 10 times (separately in each cohort), resulting in 10 imputed analytic datasets, of which resulting regression coefficients were subsequently pooled. To explore potential mechanism, we mutually adjusted for DASH and E-DII scores in the same model. To investigate potential threshold influence, we also modeled the dietary scores in quartiles for statistically significant associations. We investigated whether infant sex is a potential modifier for the associations of maternal dietary quality and inflammatory potential with birth outcomes by including the multiplicative interaction term into the model one at a time. This was done using participant-level data at each cohort, and the within-cohort interaction estimates were subsequently pooled.
007, 0. 031, and 0. 001, respectively). Upon closer inspection, the influence of higher prepregnancy DASH versus longer birth length seemed to level off at the highest quartile, whereas higher prepregnancy DASH versus higher abdominal circumference and higher early-pregnancy DASH versus lower risk of LBW relationship appeared to level off after the second quartile, as compared with those in lowest quartile (see S18  As the ROLO study has estimates with very wide confidence intervals that impaired data visualization, it was excluded from this figure. By design, the ROLO study recruited mothers who have previously delivered a macrosomic infant, thus infants born low birth weight or SGA in this study were rare (<1%), causing unstable estimates. However, it should be noted that excluding this study did not affect the pooled estimates and overall conclusion [pooled OR (95% CI) = 1.
Despite substantial efforts spent to reduce clinical heterogeneity by harmonizing data across included studies, especially for a harmonized definition of general healthy eating and inflammatory potential, it should be kept in mind that some pooled analyses were associated with high statistical heterogeneity (in Tables  1  and 2 , percentage analyses with I 2 >50% = 26%; mostly associated with nonstatistically significant pooled estimates). This could be due to residual clinical and methodological heterogeneity, or that the true effects may vary from study to study-an assumption of our chosen random-effects model. To further reduce heterogeneity, a prospectively planned IPD with harmonized study design should be conducted. Dietary data were self-reported (though with mostly validated questionnaires) before the outcomes, which might have increased nondifferential measurement errors that may bias results toward the null.
Acknowledgments Whole consortium: The authors acknowledge all investigators working on the ERA-HDHL  ALPHABET  Project and are grateful to all the families in the participating cohorts. ALSPAC: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. Please note that the ALSPAC study website contains details of all available data is available through a fully searchable data dictionary and variable search tool (http:// www. bristol. ac. uk/alspac/researchers/our-data/). EDEN: The authors thank the EDEN mother-child cohort study group, whose members are I.
A total of 1 × 10 5 THP-1 LUCIA monocytes were treated for 24 h with QNX-sLXms, vehicle, or appropriate controls (1 pM to 1 mM). After 24 h, supernatants were collected and LDH release was assayed. (a) Single-point analysis of controls defines a "high" (red area), "moderate" (yellow area), and "low" (gray area) level of cytotoxicity. (b) Concentration-response and best-fitting curves of (R)-6 and (S)-6. Data are expressed as % LDH release relative to LPS ± SEM (n = 3). Statistical analysis was carried out using Student's unpaired two-tailed t-test of the tested compound vs LPS (**p < 0. 01; ***p < 0. 001; ****p < 0. 0001). cytokines (IL-6, IL-1β, and IFN-γ) and, interestingly, enhancing secretion of IL-8 from monocytes, similar to controls (1) and Dex. In Vitro Safety Study of QNX-sLXms Identifies (R)-6 as a Safe "Lead" Modulator of Inflammation.
The generated S i is potentially predictive of a translational "therapeutic" range: the higher the S i , the safer the molecule is. As summarized in Table  S4 , S i values from all tested compounds fall in a broad range (7-50). The lead compound Figure  6. Extrinsic cytotoxic profile of series (6) of QNX-sLXms. A total of 1 × 10 5 THP-1 LUCIA monocytes were pretreated for 30 min with QNX-sLXms, vehicle, or appropriate controls (1 pM-1 μM) and subsequently challenged for 24 h with 50 ng/mL LPS. After 24 h, supernatants were collected and LDH release was assayed. (a) Single-point analysis of controls defines a high (red area), moderate (yellow area), and low (gray area) level of cytotoxicity. (b) Concentration-response and best-fitting curves of (R)-6 and (S)-6. Data are expressed as % LDH release relative to LPS ± SEM (n = 3).
Total leukocytes were stained with CD11b-APC. Using appropriate isotype controls, quadrants were drawn and data were plotted on logarithmic-scale density-or dot-plots to investigate the relative % of PMNs and monocytes/macrophages by flow cytometry. The relative proportion of each cell type was found not to be  altered by treatment with either Dex or sLXms (data not shown). (R)-6 Reduced Acute Inflammatory Response to Carrageenan Paw Swelling. In a murine model, carrageenan injection (1%) induced a self-limiting inflammatory response (paw swelling) that resolved after 72 h. The peak of inflammation was observed at 24 h as previously described. 57 nflammation was markedly attenuated in animals treated with (R)-6 (2 μg/kg, ip): the peak response observed was significantly reduced (p < 0. 05) relative to that seen in vehicle-treated animals (Figure  10 ).
Effects of (R)-6 on intracellular calcium flux in stably transfected HEK-293. Cells were cultured for 18 h prior to labeling with Fluo-4 (37 °C, 1 h). (a) Quantification of three independent experiments was carried out by calculating differential calcium signals measured at the baseline and at maximum peak. Data are expressed as % delta calcium-induced fluorescent signal relative to the peak of a known full agonist (1) ± SEM (n = 3). Concentration-response curves for LXA 4 (1) and sLXms (10 pM to 100 nM) show the E max (black circles) and predicted EC 50 (white dotted circles). Statistical analyses were carried out using Student's unpaired t-test of the tested compound vs veh (not shown). activity. Therefore, the acetonides (17) were excluded from further characterization. Among the six remaining QNX-sLXms tested, the quinoxaline analogue containing an alkyl chain of the same length as 1 (6C chain) was shown to be approximately twice as effective as 1, thus conferring (R)-6 with a general PD score of "+5" relative to the native compound.
01 mL) were added, and the reaction mixture was stirred under 10 bar of H 2 for 24 h. The mixture was concentrated and purified by silica gel column chromatography (10:1 pentane/EtOAc), and product (1S)-14 was isolated as a pale-yellow solid (27 mg, 54%). Mp = 78-81 °C; [α] D = -7. 22 (c = 1. 5 in CHCl 3 ); ee = 97% as determined by SFC using a Chiralpak IC column (CO 2 /MeCN, gradient 99:1 0-1 min and then gradient to 60:40 until 5 min, 3 mL/min), R t = 3. 00 min (S)-enantiomer, 3. 41 min (R)-enantiomer. Identical in all other physical data to the previously prepared racemic 14. (R)-1-(3-Chloroquinoxalin-2-yl)hexan-1-ol ((1R)-14). Quinoxaline ketone 11 (100 mg, 0. 381 mmol, 1 equiv) was dissolved in i PrOH (3 mL). RuCl 2 [(S)-xylbinap][(S)-DAIPEN] (23 mg, 0. 019 mmol, 0. 05 mmol), t BuOK (11 mg, 0.
095 mmol, 0. 25 equiv), and triisopropyl borate (0. 02 mL) were added, and the reaction mixture was stirred under 10 bar of H 2 for 18 h. The mixture was concentrated and purified by silica gel column chromatography (10:1 pentane/EtOAc), and product (1R)-14 was isolated as a pale-yellow solid (40 mg, 40%). Mp = 78-81 °C; [α] D = +13. 49 (c = 1. 5 in CHCl 3 ); ee = 98% as determined by SFC using a Chiralpak IC column (CO 2 /MeCN, gradient 99:1 0-1 min and then gradient to 60:40 until 5 min, 3 mL/min), R t = 3. 00 min (S)-enantiomer, 3. 41 min (R)-enantiomer. Identical in all other physical data to the previously prepared racemic 14. 1-(3-Vinylquinoxalin-2-yl)hexan-1-ol (15). Pd(PPh 3 ) 4 (31 mg, 5 mol %) and LiCl (80 mg, 1. 887 mmol, 4 equiv) were dissolved in dry 1,4-dioxane (2 mL). Aryl chloride 14 (121 mg, 0.
■ ACKNOWLEDGMENTS M. d. G. was supported by an  Irish Research Council (IRC) Government of Ireland Postdoctoral Fellowship  ( GOIPD/ 2017/1060 ) and also received funding from the  Science Foundation Ireland [PI Award  to P. G. ( 11/PI/1206 ) and  15/ IA/3152 ] and a  Strategic Research Award  from  JDRF ( 2-SRA-2017-507-S-B ). The  National Health and Medical Research Council (NHMRC) of Australia  is gratefully acknowledged. C. T. , K. G. , and A. Z. gratefully acknowledge funding from the  Science Foundation Ireland  ( PI award  to P. G. ( 11/PI/1206 )). E. B. is supported by a  University College Dublin Ad Astra Fellowship. ■ ABBREVIATIONS.
METHODS Study Design and Patient Characteristics The data that support the findings of this study may be made available from the corresponding author on reasonable request. The study protocol and main findings of REDUCE-IT have been previously published. 11, 12 REDUCE-IT was an international, phase IIIB, double-blind trial in which statin-stabilized patients were randomized 1:1 to receive either 4 g daily icosapent ethyl or placebo. All sites received ethics approval from relevant institutional review boards, and informed consent was obtained. All enrolled patients were required to be on a stable statin dose for at least 4 weeks at baseline with an LDL-C between 41 mg/dL and 100 mg/dL and a triglyceride level between 135 mg/dL and 500 mg/dL. Severe heart failure, active severe liver disease, planned coronary intervention or surgery, glycohemoglobin level greater than 10.
Total events analysis was conducted using a negative binomial model to calculate rates and rate ratios (RR) and 95% CIs. Additionally, as a supportive analysis, the Li and Lagakos-modified Wei-Lin-Weissfeld method was used to calculate HR and 95% CIs for time to the first or second events and negative binomial model for third+ events. All statistical analyses were conducted using SAS version 9. 4 software.
As observed for primary end point events, there were significant reductions in key secondary end point first events (HR, 0. 70 [95% CI, 0. 56-0. 87]; P=0. 002) and second events (HR, 0. 66 [95% CI, 0. 48-0. 89]; P=0. 007), resulting in significant reductions in total (first plus subsequent or recurrent) key secondary end point events (RR, 0. 63 [95% CI, 0. 48-0. 82]; P=0. 0008; Figure  S1 ). Hierarchical testing of primary and secondary end points was according to a prespecified sequence. A forest plot demonstrating this hierarchical sequence in Event curves for the primary efficacy end point (a composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, coronary revascularization, or unstable angina). Total event curves are based on the total adjudicated event dataset without accounting for multiple end point events occurring in a single calendar day as 1 single event.
Safety and Adverse Events Consistent with the full REDUCE-IT study population, comparable rates of total treatment-emergent adverse events and events leading to study drug withdrawal were documented between the treatment groups. Bleedingrelated adverse events were greater with icosapent ethyl in the patients with a history of CABG. Also, in accordance with the full study population, patients with a history of CABG randomized to icosapent ethyl had higher rates of atrial fibrillation or flutter requiring hospitalization for at least 24 hours (5. 0% vs 3. 1%; P=0. 03). Additional safety-and adverse event-related data are provided in Tables  S4 through S7.
DISCUSSION In this subgroup analysis of REDUCE-IT, daily treatment with 4 g of icosapent ethyl led to a statistically significant 24% reduction in the risk of first primary composite end Analyses are based on the total adjudicated event dataset without accounting for multiple end point events occurring in a single calendar day as 1 single event. HRs and 95% CIs for between treatment group comparisons were generated using Li-Lagakos-modified Wei-Lin-Weissfeld method for the first and second event categories. RRs and 95% CIs for between group comparisons used a negative binomial model for additional events beyond first and second occurrences (ie, third event or more and overall treatment comparison). Patients randomized to the study drug had significantly fewer occurrences of first, second, third or more, and total primary efficacy end point events.
69 Of particular interest, at 5 years postoperatively, OMT was not only an independent predictor of survival, but also appeared to have a more significant treatment effect than the mode of revascularization. 68 espite these clear benefits, there remains an inadequate level of OMT usage in postrevascularization patients. Among the SYNTAX population, only 41. 3% and 46. 1% of patients were taking OMT at discharge and at 5 years, respectively; these numbers were consistently lower among CABG-treated patients compared with their percutaneous coronary intervention-treated counterparts. 68, 69 ] [72]  The generalizability of REDUCE-IT findings in patients with a history of CABG has been evaluated using the Quebec Heart Database. In a large (N=12 641), contemporary, Canadian cohort of patients on statin therapy with a history of CABG, 21.
MATERIALS AND METHODS To explore the aforementioned points, I will draw on data collected during an 18-month ethnographic fieldwork divided into three research stays, between 2008 and 2013. By providing thick descriptions of intricate cultural factors and interactional contexts shaping the hallucinogenic experience, the ethnographic method offers valuable insights to answer the questions explored in this article. By allowing for both first-person data collection (through participative observation) and third-person data collection (through interviews and observation of daily interactions), this offer some other major advantages. The cross-referencing of these two types of data offers indeed highly detailed informations about the phenomenological features of the psychedelic experience and makes moreover possible to build robust hypothesis about the interactional dynamics that shape it  17.
Although this may be a practical approach, based on nine datasets from food effect studies (seven drugs) in adults vs infants and young children reported in the literature  [61, 62] , only one study highlighted a similar food effect in infants and in adults  [62] , as highlighted by Statelova et al. [40]. The same draft guidance suggests that when the pediatric formulation is not similar to the adult formulation, food effects could be evaluated in adults. This would be achieved by using foods commonly consumed with drugs by pediatric patients (e. g. formula for infants, apple sauce for toddlers) and extrapolating the results to the pediatric population  [60]. However, it has been shown by Statelova and colleagues that food effects on drug absorption in infants may not be adequately evaluated from the data collected as suggested by regulatory agencies for adult drug products, even for drugs with non-problematic absorption, no intestinal permeability limitations, highly soluble in the small intestine, no documented intraluminal interactions with food components and administered in simple dosage forms  [63].
The investigated dosing conditions included administration of pediatric drug formulations under fasted conditions, fed conditions as proposed by current regulatory guidelines for adults (30 min after the start of the consumption of the reference meal) and conditions mimicking dosing in infants where the drug formulation was administered during infant formula consumption, i. e. infant-formula fed conditions. That study revealed reduced early exposure of paracetamol and ibuprofen after administration under infant fed conditions, compared to the administration under the fasted or reference meal fed conditions in adults. In addition, using PBPK modeling, successful predictions of observed paracetamol plasma concentration (C p ) levels in infants were achieved when extrapolating from fasted conditions and infant-fed conditions adult data whereas data collected following the consumption of the FDA breakfast appeared to be less useful  [63].
Second, patient PK data for different relevant diseases should be gathered. A first set of modeling work of these PK data should be performed using existing tools such as GastroPlus© or Simcyp© based on the diseasespecific factors obtained from the first stage of the review also including common co-morbidities. These modeling efforts will help to identify gaps by means of understanding PK performance in these patients as well as provide a first validation of initial computer models. In a next stage, novel in vivo mechanistic studies in patients are needed to test novel hypotheses and fill knowledge gaps generated through the initial modeling work. This data set will improve the PBPK models for the different disease stages and a final re-validation should be performed. This approach may also be applied to disease areas outside CVRM, if successful.
e. GIT transit time, fluids composition and permeability). In order to obtain a better understanding of solubility and dissolution in the GIT of IBD patients, GIT fluids should be collected and characterized. Characterization typically includes pH, osmolality, bile salt composition/concentration, surface tension and buffer capacity. Available data is scarce, but it is being generated: e. g. the ascending colonic fluids of UC patients in relapse or remission have been characterized  [95]. Such fluids can be used for the characterization of new drugs, specifically intended for IBD patients, or for the optimization of simulated IBD GIT fluids that could be integrated in dissolution tests linked to PBPK models. For example, biorelevant media representative of the stomach, intestine and colon of IBD patients were developed and used to assess the risk of altered luminal drug solubility depending on the physicochemical properties (ionization, lipophilicity) of the drug  [96, 97].
In this case, factors such as transit time and pH will impact in vivo performance, if altered by disease. Finally, PK data should be collected comparing the IBD patient populations and healthy volunteers, potentially using formulations with targeted drug release profiles. In vitro and PBPK models should be further developed and validated, based on the obtained insights from the clinic. These tools should include all the pathophysiological changes relevant for drug absorption in patients with IBD compared to healthy subjects.
Although we do not have detailed information regarding the mechanisms by which the intestinal inflammation induces the overexpression of ACE2 receptors in the GIT, it appears that modulation of the local intestinal renin-angiotensin system (RAS) with ACE inhibitors or receptor antagonists could attenuate inflammation and COVID-19 progression  [105] [106] [107]. Multiple datasets of single-cell RNA-seq analysis indicated that SARS-CoV-2 infection of the GIT, by altering the levels of ACE2 at the brush border, may cause microbial dysbiosis and inflammation with important implications for oral drug absorption  [108]. High ACE2 expression in cholangiocytes and to a lesser extent in hepatocytes also suggests possible hepatobiliary infection by SARS-CoV-2  [109]. Current data evidenced that the SARS-CoV-2 infection may also be accompanied by mild to severe hepatic damage, resulting in increased activity of liver enzymes, higher serum bilirubin levels, and microvesicular steatosis.
For example, dissolution and precipitation assays that mimic more closely GIT conditions (transfer dissolution systems) and include the solid-state characterization of residual solids in the experiments might be needed. Additional more complex measurements that look at the impact of amorphization/crystallization and supersaturation on membrane flux should be considered. In addition, new developments in the spectroscopic field should be implemented to allow for more systematic solid-state characterization of non-dissolved residues  [215, 216]. Systematic generation of such datasets and improved in vitro -in vivo correlation can lead to better positioning of the different screens in the development process. Furthermore, this will provide "validation" of the predictive nature of in vitro testing, hence clearing the path to reduce the empirical in vivo screening.