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Ad libitum vending machine diet. | chocolate milk | For the last 3 days of each inpatient stay, participants were given ad libitum access to a computerized vending machine (StarFood, Necta). The macronutrient self-selection paradigm procedure (MSSP) was used to select items for stocking the vending machine (Vending machines were stocked with traditional breakfast, lunch, dinner, and snack items. Beverages and condiments were also included in the vending machine, and consumption of these items was also recorded. SSB included fruit juices, lemonade, chocolate milk, and regular sodas. Each participant had access to 1 vending machine that only they could access. Once foods were selected, participants were instructed to eat in the dining area, and no food was allowed in the participant’s room. All uneaten food and wrappers were returned to the Metabolic Kitchen to be weighed. The vending machines were restocked daily at 8 a.m. with items that had been removed in the previous 24 hours. All foods were weighed to the nearest tenth of a gram on a digital scale (Mettler Toledo MS Series) prior to placing them in the computerized vending machine, and the remainder of any uneaten foods were weighed after consumption. Energy and macronutrient composition of the foods consumed from the vending machine were calculated using a computerized nutrition database (ProNutra, Viocare Inc.).Vending machine foods were retrospectively categorized as either ultraprocessed or non-ultraprocessed based on NOVA categories (Statistical analyses of caloric intake from Vending Machines were performed using IBM SPSS Statistics (28.0.1.1). Repeated-measure mixed model analyses were used to assess differences in intake of energy, macronutrients, and percent of calories from MSSP and SSB among 17 participants completing both 3-day ad libitum periods. | PMC10371234 |
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MRI | REGRESSION, SENSITIVITY | On the afternoon following the morning PET scanning, high-resolution anatomical brain MRI was acquired with a HDx General Electric 3 Tesla scanner (echo time [TE] = 2.7ms, repetition time [TR] = 7.24 ms, flip angle 12°, voxel size 0.937 Under each diet condition, all subjects were scanned at 18:00, 4.5 hours after a standardized, diet-appropriate meal. Functional and structural imaging was performed on a 3T General Electric scanner and a GE 8-channel receive-only head coil. High-resolution anatomical images were collected prior to functional scanning runs (TE = 2.7 ms, TR = 7.24 ms, flip angle: 12°, voxel size: 0.937 × 0.937 × 1.2 mm). For the functional scans, 206 magnetic resonance (MR) volumes were acquired. Each echoplanar image (EPI) consisted of 44 2.8 mm slices (TE = 27 ms, TR = 2,500 ms, flip angle = 90°, voxel size = 3.4375 × 3.4375 × 2.8 mm). All structural and functional images were collected with a Sensitivity Encoding (SENSE) factor of 2 used to reduce image collection time (for structural images) or minimize image distortions (in functional images) while reducing gradient coil heating over the course of the scan session.The fMRI task is described in detail elsewhere (Analyses of functional neuroimaging were performed in AFNI (AFNI_20.2.00 ‘Aulus Vitellius’). Each individual’s anatomical MRI was transformed into the Talairach space, and the transformation matrix was applied to the functional data during preprocessing. All functional volumes were aligned to a common base EPI represented by the third volume of the first functional run. The first 3 volumes of each EPI run were trimmed to allow the fMRI signal to reach steady state. A slice-time correction was applied to all functional volumes, which were also smoothed with a 6 mm full-width half-max Gaussian kernel. Additionally, the signal value for each EPI volume was normalized to the percent signal change from the voxel’s mean signal across the time course.Individual subject data were checked for quality assurance, and outlying time points resulting from head motion were censored from the analyses. At the individual level, multiple regression was used to analyze the data, with regressors of noninterest included in the model to account for each run’s signal mean, linear, quadratic, and cubic signal trends, as well as 6 motion parameters (3 translations and 3 rotations) saved from the image registration step during preprocessing. The food pleasantness task regressor was constructed by convolving a box-car function with a width of 5 seconds beginning at the onset of the food image with a gamma-variate function to adjust the predictor variable for the delay and shape of the BOLD response. Given similarities in pleasantness ratings across diet conditions ( | PMC10371234 |
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PET | TRANSMISSION, SEPARATION, RESOLUTION | PET scanning was performed using a High Resolution Research Tomograph (HRRT; Siemens Healthcare) a dedicated brain PET scanner with a resolution of 2.5–3.0 mm and a 25 cm axial field of view. Transmission scanning was performed with a 137Cs rotating pin source to correct for attenuation. Two hours after a standard breakfast, a bolus of approximately 5 mCi of [18F]fallypride was infused i.v. using a Harvard pump. The specific activity was approximately 2,000 mCi/μmol at time of injection, and the radiochemical purity of the radiotracer was > 99%. PET emission data were collected starting at radiotracer injection over 3.5 hours, in 3 blocks separated by 2 10-minute breaks. Thirty-three volumes were acquired at times 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12.5, 15, 20, 25, 30, 40, 50, 60, 90, 110, 130, 170, and 200 minutes. During each scan block, the room was quiet and dimly lit, and each subject was instructed to keep their head as still as possible, relax, and try to avoid falling asleep. The image reconstruction process corrected for head motion, which was tracked throughout each scan. Each scan consisted of 207 slices (slice separation = 1.22 mm). The fields of view were 31.2 cm and 25.2 cm for transverse and axial slices, respectively.The PET images were aligned within each scan block with 6-parameter rigid registration using seventh-order polynomial interpolation, and each block was aligned to the volume taken at 20 minutes of the first block. The final alignments were visually checked, with translations varying by < 5 mm and the rotations by < 5 degrees. | PMC10371234 |
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Statistics | Power calculations were based on cross-sectional data, not within-subject repeated measurements of D2BP change and fMRI response in response to dietary manipulation, which had not previously been measured. To detect a meaningful difference of effect size in D2BP (ratio of the expected mean and the standard deviation of the paired differences), with 20 subjects measured, we estimated that the study would achieve a power of 98% via the paired samples fMRI images were included in AFNI’s 3dttest++ to identify clusters of significant effects of the diet condition (RF > Baseline for Individual participants’ anatomical MRI images (see above) were coregistered to the aligned PET images by minimizing a mutual information cost function for each individual participant. For the analyses described in the main text, each individual’s anatomical MRI was linearly transformed into the Talairach space, and the transformation matrix was applied to the PET images, which were then smoothed with a 5 mm full-width, half-max Gaussian kernel. Data were exported to MATLAB where time-activity curves for [18F]fallypride concentration in each voxel were fit to a kinetic model (with the cerebellum used as the reference tissue) to determine D2BP (Participants’ D2BP maps were included in AFNI’s 3dttest++ identify clusters with significant effects of diet (RF>Baseline for To test the robustness of our results with respect to alterations in processing and analysis pipeline, we also analyzed the data Individual participants’ anatomical MRI images were coregistered to the aligned PET images by minimizing a mutual information cost function for each individual participant. The aligned PET images were smoothed with a 5-mm full-width, half-max Gaussian kernel. Data were exported to MATLAB, where time-activity curves for [18F]fallypride concentration in each voxel were fit to a kinetic model with the cerebellum used as the reference tissue to determine D2BP ( | PMC10371234 |
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Study approval | Diabetes & Digestive & Kidney Diseases | All study procedures were approved by the IRB of the National Institute of Diabetes & Digestive & Kidney Diseases. Written informed consent was received prior to participation, and compensation was provided. | PMC10371234 |
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Author contributions | PH, WKS | KDH, ABC, WKS, PH, and AM designed the research study. WKS, JAA, JEI, and ABC conducted experiments and acquired data. VLD, JG, ABC, IG, JAA, and WKS analyzed data and performed statistical analysis. VLD and KDH drafted the manuscript. All authors contributed intellectually and approved the manuscript. | PMC10371234 |
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Supplementary Material | PMC10371234 |
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Supplemental data | PMC10371234 |
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ICMJE disclosure forms | PMC10371234 |
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06/22/2023 | Electronic publication | PMC10371234 |
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Study design. | obesity | OBESITY | Seventeen men and women with obesity were admitted as inpatients to the Metabolic Clinical Research Unit at the NIH Clinical Center. They completed fMRI and PET scans on the third day of a 5-day inpatient eucaloric baseline diet, after which they were randomized to either a 30% reduced-calorie diet achieved by selective restriction of dietary fat (RF diet) or carbohydrate (RC diet). Neuroimaging was repeated on the fifth day of the reduced-energy diet, after which, on days 12–14 of the inpatient stay, participants consumed food ad libitum from vending machines. After a 2- to 4-week washout period, participants were readmitted as inpatients to complete the 5-day eucaloric baseline diet, and neuroimaging was repeated on the fifth day of the alternate 30% reduced calorie diet. During the final 3 inpatient days, participants again consumed food ad libitum from vending machines. | PMC10371234 |
Selective reduction of dietary fat, but not carbohydrates, alters brain activity in reward regions. | ( | PMC10371234 |
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Characteristics of participants completing baseline and portions of neuroimaging during reduced-calorie interventions. | PMC10371234 |
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Locations of clusters displaying changes in BOLD responses within a priori reward-region mask or D2BP to reduced-fat or -carbohydrate diets. | PMC10371234 |
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Ad libitum intake over 3 days from vending machines after RF and RC diets. | PMC10371234 |
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Background and Aims: | primary biliary cholangitis | PRIMARY BILIARY CHOLANGITIS | ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). | PMC10344437 |
Approach and Results: | NASH, pruritus, NRS | SECONDARY | Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( | PMC10344437 |
Conclusions: | pruritus, primary biliary cholangitis, PBC | PRIMARY BILIARY CHOLANGITIS, PBC | Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.
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INTRODUCTION | abnormal serum liver tests, inflammation, granulomatous lymphocytic cholangitis, cholestatic, liver injury, bile duct injury/cholangitis, fibrosing liver injury, PBC, cholestasis, pruritus, NASH, primary biliary cholangitis, hepatitis, Histologic damage | DISEASE PROGRESSION, PBC, PRIMARY BILIARY CHOLANGITIS, INFLAMMATION, DISEASE, CHOLESTASIS, HEPATITIS | People living with primary biliary cholangitis (PBC) frequently have impaired quality and quantity of life, resulting from a chronic autoimmune-mediated, cholestatic, and fibrosing liver injury.Histologic damage characterized by a granulomatous lymphocytic cholangitis is associated with abnormal serum liver tests, including elevated serum alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), aminotransferase activity, and total bilirubin.Seladelpar is a potent and selective peroxisome proliferator-activated receptor (PPARδ) agonist that has been shown to decrease levels of biochemical markers of cholestasis, liver injury, and inflammation in patients with PBC.The objective of this phase 3 study was to evaluate the safety of seladelpar 5 and 10 mg QD and to assess its effect on ALP, total bilirubin, biochemical markers of disease, and pruritus in patients with PBC at high risk for disease progression. The study originally aimed to evaluate treatment through 12 months; however, it was terminated early due to unexpected histological findings (ie, portal inflammation and interface hepatitis with plasma cells, bile duct injury/cholangitis, vascular changes, and other miscellaneous findings) in a concurrent study of seladelpar in patients with NASH (NCT03551522). A detailed independent investigation by a committee of pathologists and hepatologists determined that the histological findings following seladelpar treatment in the NASH trial did not differ qualitatively from baseline and were unrelated to seladelpar. | PMC10344437 |
METHODS | PMC10344437 |
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Patients | PBC | Patients aged 18 to 75 years diagnosed with PBC [≥2 of the following criteria: history of ALP > ULN for ≥6 months, positive antimitochondrial antibody titers (>1/40 on immunofluorescence or M2-positive by ELISA) or PBC-specific antinuclear antibodies, or documented liver biopsy histology consistent with PBC] were screened for eligibility. Patients with ALP ≥1.67×ULN and total bilirubin ≤2×ULN were eligible. | PMC10344437 |
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Study design | This phase 3, double-blind, randomized, placebo-controlled study was conducted at 111 sites in 21 countries. The protocol was approved by appropriate local and national institutional review boards or independent ethics committees, and the trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent. The trial was preregistered (www.clinicaltrials.gov; NCT03602560). Pol Boudes, Christopher L. Bowlus, Gideon M. Hirschfield, Cynthia Levy, Marlyn J. Mayo, Alexandra Steinberg, John M. Vierling, Charles A. McWherter, and Yun-Jung Choi provided input to study design that led to the protocol. Gideon M. Hirschfield, Charles McWherter, and Yun-Jung Choi had access to all data and reviewed and can vouch for the integrity of the data analyses. | PMC10344437 |
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Original study design | pruritus, NRS | The study was initially designed as a 12-month study where eligible patients were centrally randomized 1:1:1 through an interactive voice/web response system to receive seladelpar (CymaBay Therapeutics, Inc., Newark, CA) 5 or 10 mg QD orally or matching placebo following a 2-week screening period and subsequent 2-week run-in period. Patients and investigators were blinded to treatment, and blinding was maintained using a matched placebo. Patients were stratified by ALP level (<350 or ≥350 U/L) and pruritus numerical rating scale (NRS) (< 4 or ≥ 4). Patients receiving seladelpar 5 mg were to be uptitrated to 10 mg QD if they had not met the primary end point at month 6. Randomization occurred between November 26, 2018, and November 12, 2019. | PMC10344437 |
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Amended analysis plan | NASH | Because of unexpected histological findings in a concurrent phase 2 study of seladelpar in patients with NASH, dosing in ENHANCE was interrupted on November 25, 2019, and the study was terminated prematurely on December 20, 2019. The biopsy tissues and full clinical profile of each patient in the NASH trial were reviewed by an independent committee of pathologists and hepatologists who concluded that the histological features of concern were also observed in baseline biopsies and were unrelated to seladelpar treatment. | PMC10344437 |
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Study assessments | pruritus, itching, Cancer | ADVERSE EVENTS, ADVERSE EVENT, CANCER | Study assessment visits were performed at screening; run-in; day 1 (randomization); months 1, 3, and 6; and at a follow-up visit 4 weeks after the end of treatment. Fasting blood samples were obtained at each visit for ALP, total bilirubin, other biochemistry, lipids, bile acid precursor 7α-hydroxy-4-cholesten-3-one (C4), IgM, and hematology assays. Patients recorded a daily pruritus NRS each evening for the previous 24 hours on a scale of 0 (no itching) to 10 (worst imaginable itching) using an e-diary from the run-in visit through the month 6 visit.Safety assessments included physical examinations, vital sign evaluations, and laboratory tests. Treatment-emergent adverse events (TEAEs) were summarized using Medical Dictionary for Regulatory Activities version 21.0 and graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. | PMC10344437 |
Primary end point | The primary end point was a composite biochemical response defined as ALP <1.67×ULN, ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN | PMC10344437 |
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Secondary end points | pruritus | SECONDARY | Key secondary end points were the proportion of patients with ALP ≤1.0×ULN (normalization) at month 3 and the change in pruritus NRS from baseline at month 3 in patients with baseline pruritus NRS ≥4, which was considered symptomatic. | PMC10344437 |
Statistical analysis | pruritus | SECONDARY | A sample size of 80 patients per treatment group, or 240 patients total, was estimated to provide (1) >90% power to detect a difference in the composite end point response rate (based on estimated response rates of <15%Efficacy was assessed in the modified intent-to-treat (mITT) population, which included all randomized patients who received ≥ 1 dose of study drug, and was analyzed based on randomized treatment. Efficacy analyses were conducted on the (mITT) population excluding patients who discontinued treatment before the month 3 assessment due to study closure. Patients who discontinued treatment before an assessment time point due to reasons other than study closure and did not have an assessment at the specified time point were classified as nonresponders. Safety was assessed during the study in all randomized patients who received ≥1 dose of study drug and was analyzed based on treatment received.Statistical comparisons of efficacy end points included the seladelpar 10- and 5-mg groups versus the placebo group and the seladelpar 10-mg group versus the 5-mg group for the primary and key secondary end points and mean change from baseline in ALP. Statistical tests were conducted using 2-sided tests at a 0.05 level of significance. The primary end point and ALP normalization response rate were analyzed using the Cochran-Mantel-Haenszel test adjusted for randomization stratification variables. Baseline pruritus NRS was defined as the mean of daily recorded scores during the run-in period. Assessment of pruritus NRS change from baseline compared the weekly averaged pruritus NRS of patients with a baseline score ≥4 using an analysis of covariance (ANCOVA) model. Least squares mean percent change from baseline for serum biochemistries was estimated using an ANCOVA model with percent change from baseline as the dependent variable, treatment group and randomization stratification factors as fixed effects, and baseline as a covariate. | PMC10344437 |
RESULTS | PMC10344437 |
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Patient disposition | primary biliary cholangitis, cholestasis | PRIMARY BILIARY CHOLANGITIS, CHOLESTASIS, DISEASE CHARACTERISTIC, PBC | Among 501 patients screened, 265 were randomized to receive placebo (n=87) or seladelpar 5 mg (n=89) or 10 mg (n=89). Two patients completed study treatment through month 12; 255 of 265 (96.2%) patients discontinued treatment due to study closure, 6 (2.3%) discontinued due to TEAEs, 1 (0.4%) withdrew consent, and 1 (0.4%) was lost to follow-up (Figure Patient flowchart. Screen failures (a patient may be counted in >1 reason for failure): alkaline phosphatase < 1.67× upper limit of normal (ULN) n=149, estimated glomerular filtration rate <60 mL/min/1.73 mBaseline demographics and disease characteristics, including biochemical markers of cholestasis, were well balanced among treatment groups (Table Patient baseline demographics and clinical characteristics
Includes American Indian or Alaska Native, Asian, and Black or African American.All listed medications except UDCA were discontinued before study entry.Steroids, immunosuppressants, methotrexate, systemic steroids, and colchicine.Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; n, number of patients in the category; N, number of patients in the treatment group; NRS, numerical rating scale; PBC, primary biliary cholangitis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. | PMC10344437 |
Efficacy | PMC10344437 |
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Composite biochemical response and ALP normalization | At month 3, significantly greater proportions of patients in the seladelpar 5-mg (57.1%, Proportion of patients who achieved the composite biochemical end point at month 3. Composite end point was defined as alkaline phosphatase (ALP) serum levels < 1.67× upper limit of normal (ULN), ≥15% decrease in ALP serum levels, and total bilirubin serum levels ≤ ULN. The proportion of patients attaining ALP normalization at month 3 (≤1.0×ULN) was greater in the seladelpar 10-mg (27.3%) group versus the placebo (0%, Proportion of patients who achieved alkaline phosphatase (ALP) normalization at month 3 ALP normalization. ALP normalization was defined as serum levels ≤1.0×upper limit of normal. Examining the individual composite end point components, at month 3, 18% of patients in the placebo group, 64% in the seladelpar 5-mg group, and 82% in the seladelpar 10-mg group achieved ALP < 1.67×ULN, and 23%, 95%, and 95%, respectively, achieved a ≥ 15% decrease from baseline in ALP (Supplemental Table S2, | PMC10344437 |
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Pruritus | SE, pruritus, itch, NRS | Among patients in the prespecified subgroup with moderate-to-severe pruritus (pruritus NRS ≥4) at baseline who were evaluable at month 3 (placebo, n=18; seladelpar 5 mg, n=17; and seladelpar 10 mg, n=18), the mean decrease from baseline in pruritus NRS was significantly greater in the seladelpar 10-mg (−3.14, Absolute LS mean (SE) change from baseline in pruritus numerical rating scale (NRS) at month 3 (A) and proportion of patients who achieved point reductions from baseline in pruritus NRS at month 3 (B). For (A) and (B), populations included only patients with pruritus NRS ≥4 at baseline. For (A), change from baseline was estimated by an analysis of covariance model with treatment group and randomization alkaline phosphatase stratification as factors and baseline pruritus score as a covariate. For (B), patients who discontinued treatment before month 3 due to reasons other than study termination and who did not have evaluable data at month 3 were considered nonresponders. Greater changes from baseline with seladelpar versus placebo at months 1 and 3 in the 5-domain itch scale total and individual domain scores (Supplemental Figure S3A–L, | PMC10344437 |
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Liver biochemistry and lipids | Reductions (LS mean) in ALP from baseline at all time points through month 6 were greater in both seladelpar treatment groups versus the placebo group. At month 3, mean ALP decreased by 3.7% from baseline in the placebo group, whereas it decreased by 35.7% in the seladelpar 5-mg group and by 44.2% in the 10-mg group (LS mean relative (percent) change from baseline and mean absolute values for ALP (A and B) and ALT (C and D) through month 6. *Reductions from baseline in ALT were also greater in the seladelpar groups versus the placebo group at all time points through month 6, with LS mean (median) reductions of 4.0% (3.0%), 23.4% (24.3%), and 16.7% (28.3%) observed in the placebo, 5-, and 10-mg groups, respectively, at month 3 (Figure Compared with placebo, seladelpar was associated with greater improvements in other serum liver biochemical markers and in lipid levels through month 6. At month 3, LS mean reductions in total and indirect bilirubin were 6.1% and 6.5%, respectively, in the seladelpar 5-mg group and 4.0% and 6.8%, respectively, in the 10-mg group, while patients receiving placebo experienced a 0.9% increase in total bilirubin and a 1.1% increase in indirect bilirubin (Supplemental Figure S5A-B, S5E-F, At month 3, seladelpar decreased mean total cholesterol, LDL-cholesterol (LDL-C), and triglyceride levels by 3.7%, 5.6%, and 5.9%, respectively, in the 5-mg group and by 4.4%, 8.2%, and 13.1%, respectively, in the 10-mg group compared with decreases of 1.8%, 0.6%, and 0.6%, respectively, in the placebo group (Supplemental Figure S5K–P, | PMC10344437 |
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Bile acid synthesis (C4) and IgM concentrations | Seladelpar was also associated with greater LS mean reductions in serum levels of C4 and IgM at months 1 and 3 compared with the placebo group (Supplemental Table S5, | PMC10344437 |
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Safety | cirrhosis, pruritus, SD, insomnia | ATRIOVENTRICULAR BLOCK, RHEUMATOID ARTHRITIS, CIRRHOSIS, ADENOID CYSTIC CARCINOMA, ADVERSE EVENT | Mean (SD) duration of exposure was 17.7 (11.7) weeks in the total population. The large SD is due to the early termination of the study with patients having a wide range of treatment durations. Overall, the proportion of patients with ≥1 TEAE was greater in the placebo group (73.6%) versus either the seladelpar 5-mg (62.9%) or 10-mg (65.2%) groups (Table Summary of safety eventsAbbreviations: n, number of patients in the category; N, number of patients in the treatment group; TEAE, treatment-emergent adverse event.Six patients discontinued study drug due to TEAEs: 2 in the placebo group (increased bilirubin and atrioventricular block), 2 in the seladelpar 5-mg group (pruritus and adenoid cystic carcinoma), and 2 in the seladelpar 10-mg group (pruritus, insomnia, and rheumatoid arthritis). No grade 3 or greater elevations in serum aminotransferase activity were reported, and no muscle, renal, or pancreatic safety concerns were reported. The safety profile was comparable between patients with and without cirrhosis at baseline (Supplemental Table S6, | PMC10344437 |
DISCUSSION | itch, Pruritus, points)Seladelpar, liver injury, pruritus, PBC, deaths | DISEASE PROGRESSION, PBC, PRURITUS, DISEASE, ADVERSE EVENT | New approved therapies remain important for people living with PBC. Current agents do not optimally address disease activity or symptoms. Seladelpar is a selective PPARδ agonist that has documented anticholestatic, anti-inflammatory, and antipruritic effects.Among patients with clinically significant itch (baseline pruritus NRS ≥4), the pruritus NRS significantly decreased at month 3 with seladelpar 10 mg compared with placebo. The proportion of patients with a clinically meaningful reduction (≥2 points)Seladelpar appeared safe and well tolerated, with no deaths or grade 3 or greater ALT or AST elevations. Pruritus (qualitative) was the most common adverse event; however, incidence was highest in the placebo group.A variety of approaches are being pursued for new therapies in PBC. Direct comparisons are difficult because of study design differences. The 78.2% composite end point response rate at month 3 observed for seladelpar 10 mg in this study seems to be similar or better than those reported with other PBC therapies, including obeticholic acid,The anticholestatic, anti-inflammatory, and potentially antifibrotic properties of seladelpar are predicted to affect disease progression and improve outcomes. PPARδ is expressed in hepatocytes,A limitation of this study is its short duration due to early termination. However, although the study was stopped early and the primary composite biochemical end point was amended to 3 months, more than three-fourths of patients achieved the end point. In addition, in a phase 2 study, seladelpar efficacy observed after 3 months of treatment was sustained through 1 year, including ALP reduction and achievement of ALP normalization and composite efficacy end point.In conclusion, in this placebo-controlled, randomized trial, the potent and selective PPARδ agonist seladelpar, at an optimal dose of 10 mg daily, provided clinically significant anticholestatic effects and reduced signs of liver injury and pruritus in patients with PBC. Treatment was not associated with emergent safety concerns. The efficacy and safety profile of seladelpar in this and previous studies suggests its potential use as second-line therapy to address disease activity and symptoms. A 52-week, phase 3, randomized, placebo-controlled, registration study to confirm seladelpar 10 mg QD efficacy and safety is ongoing (NCT04620733). | PMC10344437 |
Supplementary Material | PMC10344437 |
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SUPPLEMENTARY MATERIAL | PMC10344437 |
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DATA AVAILABILITY | Requests for additional data should be directed to the study sponsor through the corresponding author. | PMC10344437 |
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AUTHOR CONTRIBUTIONS | Study concept and design: all; acquisition, analysis, and interpretation of data: all; and drafting and/or critical revision of manuscript for important intellectual content and final approval of manuscript: all. | PMC10344437 |
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ACKNOWLEDGMENTS | The authors thank Ke Yang and Kalyan Palla of CymaBay Therapeutics Inc., for assistance with statistical analyses and Holly Capasso-Harris of Certara Synchrogenix for writing assistance that was funded by CymaBay Therapeutics.
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FUNDING INFORMATION | PBC | PBC | This study and preparation of this manuscript were funded by CymaBay Therapeutics, which had a role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Palak J. Trivedi received institutional salary support from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC). This paper presents independent research supported by the Birmingham NIHR BRC based at the University Hospitals Birmingham National Health Service Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health.Presentation: Hirschfield GM, Kowdley KV, Shiffman ML, et al. ENHANCE: safety and efficacy of seladelpar in patients with PBC—a phase 3 international, randomized, placebo-controlled study [AASLD abstract LO11]. | PMC10344437 |
CONFLICTS OF INTEREST | cholestatic pruritus, A. McWherter, Zambon, Nordisk, Nordisk, Metacrine, PBC | PBC, MITCHELL, ONCOLOGY, EVENTS, STUART | Gideon M. Hirschfield consults for and received payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GlaxoSmithKline, Intercept Pharma, and Ipsen. He consults for CymaBay Therapeutics, Escient, Gilead, Mirum, and Pliant. Mitchell L. Shiffman consults for, is on the speakers’ bureau for, and received grants from Intercept. He consults for and is on the speakers’ bureau for Intra-Sana. He is on the speakers’ bureau for and received grants from Cymbay. He received grants from Genfit, Hightide, and Mirum. Aliya Gulamhusein consults for and is on the speakers’ bureau for Intercept. She consults for CymaBay. Kris V. Kowdley consults for, is on the speakers’ bureau for and received grants from 89 Bio, Genfit, Gilead, Intercept, and CymbaBay. He consults for and received grants from Madrigal, Mirum, NGM, Pliant, and Zydus. He consults for and owns stock in Inipharm. He consults for Calliditas and Ipsen. He is on the speakers’ bureau for AbbVie. He received grants from GSK, Pfizer, Hanmi, HighTide, Viking, and Janssen. He receives royalties from UpToDate. He received payment for expert testimony from the Department of Justice. He participated in a data safety monitoring board or advisory board for CTI, Durect, and Labcorp. He received equipment, materials, drugs, medical writing, gifts, or other services from Sonic Insight. John M. Vierling advises and received grants from CymaBay, Intercept, Lilly, Novartis, and Sagiment. He advises Arena, Blade, Kezar, Labcorp, Fractyl, Ipsen, Moderna, and Taiwan J. He received grants from Genfit. He is a board member of and owns stock in Athenex. Cynthia Levy consults for, advises, and received grants from Cara Therapeutics, CymaBay Therapeutics, and GlaxoSmith Kline. She consults for and received grants from Calliditas, Escient, Genfit, Gilead, Intercept, Ipsen, Mirum, and Target RWE. She received grants from HighTide, Novartis, and Zydus. Andreas E. Kremer consults for, received payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from, received grants from, and advises AbbVie, Bayer, CymaBay Therapeutics, Gilead, GlaxoSmithKline, Intercept Pharma, and MSD. He received payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from and received grants from AOP Orphan, Bristol Myers Squibb, CMS, Dr. Falk, Eisai, Eli Lily, Janssen, Newbridge, Novartis, and Zambon. He consults for and advises Beiersdorf, Escient, FMC, Guidepoint, Medscape, Mirum, Myr, Roche, and Viofor. Ehud Zigmond advises, received lecture fees from, and received grants from Neopharm LTD. Stuart C. Gordon consults for and received grants from CymaBay, Gilead, and GSK. He received grants from AbbVie, DURECT, Genfit, Hightide, Intercept Pharma, Merck, Mirum, Pliant, and Viking. Christopher L. Bowlus consults for and received grants from CymaBay Therapeutics, Eli Lilly, and GlaxoSmithKline. He consults for BiomX, Mirum, Shire, and Trevi Therapeutics. He received grants from Arena Pharmaceuticals, Bristol Myers Squibb, Calliditas Therapeutics, Chemomab, COUR Pharmaceuticals, Genfit, Gilead, GlaxoSmithKline, Hanmi, Intercept, Novartis, NovoNordisk, Pliant, Takeda, and TARGET. Eric J. Lawitz consults for, is on the speakers’ bureau for, and received grants from Intercept. He consults for and received grants from Akero, Boheringer Ingelheim, BMS, Novo Nordisk, Metacrine, Sagimet, and Terns. He is on the speakers’ bureau for and received grants from AbbVie and Gilead. He received grants from 89Bio Inc., Allergan, Alnylam Pharmaceuticals Inc., Amgen, Ascelia Pharma, Assemblybio, AstraZeneca, Axcella Health, Biocryst Pharmaceuticals, Bird Rock Bio Inc., Conatus Pharmaceuticals, CymaBay Therapeutics, CytoDyn, DSM, Durect Corporation, Eli Lilly, Enanta Pharmaceuticals, Enyo Pharma, Exalenz Bioscience, Galectin Therapeutics, Galmed Pharmaceuticals, Genentech, Genfit, GlaxoSmithKline, Hanmi Pharmaceuticals, HighTide Biopharma, Inventiva, Janssen Pharmaceuticals, Laboratory for Advanced Medicine, Loxo Oncology, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals Inc., Northsea Therapeutics, Novartis, Pfizer, Poxel Co., Roche, Synlogic Therapeutics, Viking Therapeutics, and Zydus Pharmaceuticals. Richard J. Aspinall consults for and is on the speakers’ bureau for Norgine UK. He is on the speakers’ bureau for Intercept UK. He owns stock in CymaBay. Daniel S. Pratt consults for Mediar Therapeutics. Karina Raikhelson received payment/honoraria for lectures presentations, speakers bureaus, manuscript writing, or educational events from Abbott Laboratories GmbH, Alfasigma Rus, Binnopharm Group, Dr. Falk Pharma GmbH, JSC Nizhfarm, and JSC Pharmstandard. She received payment/honoraria for lectures presentations, speakers bureaus, manuscript writing, or educational events and was expert witness for STPF “Polisan.” She received grants from CymaBay and Novartis. Michael A. Heneghan consulting for Ipsen, Eledon, and Moderna He recieved payment/honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events from Falk, Advanz Pharma, and Intercept Pharma. He receives royalties from UpToDate. Sook-Hyang Jeong received grants from Bristol Myers Squibb, CymaBay Therapeutics, Galmed, Gilead, Hoffmann-La Roche Ltd, Intercept, and MSD. Alma L. Ladrón de Guevara received grants from AstraZeneca, Cymabay, Lilly, Madrigal, Akero, Galectin, MSD and Novo Nordisk, and Viking. Marlyn J. Mayo consults for and received grants from CymaBay Therapeutics, GlaxoSmithKline, and Mallinckrodt. She received grants from Genfit, Intercept, Mirum, and TARGET. She consults for Ipsen. She is on the speaker’s bureau for Intra-Sana. George N. Dalekos advises, is on the speakers’ bureau for, and serves as principal investigator for Genkeyotex, Pfizer, and Sobi. He advises and is on the speakers’ bureau for Ipsen and Sanofi. He is a principal investigator for Amyndas Pharmaceuticals, CymBay Therapeutics, Intercept, Novo Nordisk, Regulus Therapeutics, and Tiziana Life Sciences. Joost P.H. Drenth consults for Camurus. He received grants from AbbVie and Gilead. He is on a data safety monitoring board or advisory board for COIN B Study. Ewa Janczewska advises and received grants from Novo Nordisk and Cellaion. She is on the speakers’ bureau for and received grants from Abbvie. She is on the speakers’ bureau for Roche. She received grants from Axella, Exelixis, CymaBay, Calliditas, BMS, GSK, Janssen-Cilag, Dr. Falk, Inventiva, and MSD. Barbara A. Leggett received grants from CymaBay Therapeutics. Frederik Nevens consults for and received grants from Gilead. He consults for Abbvie, W.L. Gore, Cook Medical, TwinPharma, Intercept, Genkyotex, Camurus, Chemomab Therapeutics, Agomab Therapeutics, Novartis Pharma, Mayoly Spindler, Calliditas Therapeutics, Norgine, Takeda, and Dynacure. He received grants from Promethera Therapeutics and Ipsen. Victor Vargas consults for Genfit. He is on the speakers’ bureau for Intercept. He is on the data safety monitoring board or advisory board for Promethera Biosciences/Cellaion. He received grants from Advanz Pharma. Christophe Corpechot consults for and received grants from Intercept and CymaBay. He consults for Genkyotex/Calliditas. He received grants from Arrow Génériques, Biotest, and Gilead. Eduardo L. Fassio received grants from Gador. Eli Zuckerman consults and is a speaker for AbbVie, Gilead, GlaxoSmithKline, Janssen, Merck, Neopharm, NovoNordisk, and Roche. He is also a speaker for Bristol Meyers Squibb and Novartis. Holger Hinrichsen consults for and received payment/honoraria for lectures, presentations, and speakers bureaus from AbbVie, Gilead, and Intercept Pharma. He received payment/honoraria for lectures, presentations, and speakers bureaus Norgine. Pietro Invernizzi advises, is on the speakers’ bureau for, and received grants from Intercept. He advises Calliditas and Zydus. He received grants from Abbvie. Palak J. Trivedi consults for and advises CymaBay. David E.J. Jones consults for, is on the speakers’ bureau for, and received funding from Intercept. He consults for CymaBay Therapeutics, Kowa, and Umecrine. He is on the speakers’ bureau for Falk, GlaxoSmithKline, and Ipsen. Mark G. Swain consults for, is on the speakers’ bureau for, and received grants from Gilead. He consults for and received grants from Pfizer and Novartis. He consults for Ipsen. He is on the speakers’ bureau for Abbott. He received grants from AbbVie, Ancella, AstraZeneca, Bristol Myers Squibb, Calliditas Therapeutics, Celgene, CymaBay Therapeutics, Galectin, Genfit, GlaxoSmithKline, Intercept, and Novo Nordisk. Alexandra Steinberg owns stock, has intellectual property rights in and was employed by CymaBay Therapeutics when the work was conducted, and is employed by Carmot Therapeutics. Pol F. Boudes was employed by CymaBay Therapeutics when the work was conducted and declares a seladelpar method of use patent for PBC. He is currently employed by Galectin Therapeutics. Yun-Jung Choi is employed by CymaBay Therapeutics. Charles A. McWherter owns stock and intellectual property rights in and is employed by CymaBay. He declares a seladelpar method of use patent for PBC and for cholestatic pruritus. The remaining authors have no conflicts to report.*Names and affiliations are listed in Acknowledgments.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, | PMC10344437 |
REFERENCES | PMC10344437 |
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Background | disordered eating | Given the heightened emphasis on physical appearance and the prevalence of social media in young women, they are particularly vulnerable to experiencing negative body image and disordered eating. Therefore, modified social media portrayals of pregnancy could cause young women to have negative attitudes toward a potential pregnancy and subsequently not properly utilize care and resources. The present study examined the influence of disordered eating and modified portrayals of pregnancy on young women’s attitudes toward a potential pregnancy and various feelings associated with pregnancy. | PMC9883907 |
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Methods | Weight Gain | The sample consisted of 154 women aged 18–30, who were given the Eating-Attitudes Test-26, randomly shown either modified or unmodified social media portrayals of pregnancy, then given the Attitudes Toward Potential Pregnancy Scale and the Gestational Weight Gain Psychosocial Risk Assessment Tool. | PMC9883907 |
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Results | weight gain, disordered eating | REGRESSIONS | A series of hierarchal regressions revealed that there were no significant main effects or interactions for young women’s attitudes toward potential pregnancy. However, women who viewed modified portrayals of pregnancy had higher self-efficacy, and women with higher levels of disordered eating had lower self-efficacy, more positive attitudes toward gestational weight gain, and lower current body image satisfaction. | PMC9883907 |
Conclusions | disordered eating and social media | These results highlight the myriad of different attitudes that young women have toward a potential pregnancy and how these attitudes are influenced by disordered eating and social media. Our findings can be used for educating caregivers and implementing intervention strategies for women. | PMC9883907 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12905-023-02177-7. | PMC9883907 |
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Plain English summary | Young women are more likely to have a negative body image and an unhealthy relationship with food because they are more focused on their physical appearance, especially with the rise of social media. If young women with these struggles see edited representations of pregnancy, they can develop a negative attitude about becoming pregnant in the future. This study examined how unhealthy eating habits and highly edited pictures of pregnant women impact young women’s attitudes toward a potential pregnancy. Our participants answered questions designed to see if they possess unhealthy eating thoughts and behaviors, then they were randomly shown either highly edited or not highly edited pictures of pregnant women from social media. Then, they answered questions about their attitude toward a potential pregnancy. We found that women with particularly unhealthy relationships with food were less confident about maintaining healthy eating habits throughout pregnancy. However, we also found that women who viewed the highly edited pictures were more confident about maintaining healthy eating habits throughout pregnancy. We can use these results to educate caregivers and help women get better care. | PMC9883907 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12905-023-02177-7. | PMC9883907 |
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Keywords | PMC9883907 |
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Background | disordered eating, eating disorder | Individuals who are highly concerned with their weight-related appearance and/or preoccupied with thoughts of eating are at-risk for developing harmful behaviors to control their eating. Such patterns of attitudes and behaviors are referred to as disordered eating (DE) [Young women (between the ages of 18 and 30) are especially vulnerable to experiencing higher levels of DE behaviors and are at high risk of developing a clinical eating disorder [Young women have reported varying feelings toward the possibility of a potential pregnancy, ranging from wanting to become pregnant to wanting to avoid pregnancy [ | PMC9883907 |
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Disordered eating | guilt, eating; compulsive eating, anxiety | PURGING, DISORDERS, ANOREXIA NERVOSA AND BULIMIA | Clinical eating disorders, such as anorexia nervosa and bulimia nervosa, affect about 5% of the general population [DE represents a variety of thoughts and behaviors that highlight a preoccupation with food, including guilt, shame, and anxiety about eating; compulsive eating; frequent fluctuations in weight; restricting food intake; and purging, eating, or over-exercising to compensate for eating [DE thoughts and behaviors typically begin to develop in adolescence, often during times of stress [DE occurs in both men and women but tends to occur more frequently in women [ | PMC9883907 |
Social media portrayals of pregnancy | Social media allows for people to edit their photos to show their most flattering selves, blurring one’s real self with a digital self [Social media portrayals of pregnancy are also subject to substantive edits. A qualitative review of pregnancy portrayals on Instagram showed that images were often professionally looking with a spotless background, perfectly edited, and intentionally posed to expose the woman’s stomach [Social media can also be damaging to pregnant women because of social comparisons to their friends and family. Some women have described that seeing friends that are smaller than them while pregnant caused them to judge themselves and have a negative impact on their body image [ | PMC9883907 |
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Attitudes toward potential pregnancy | Often, pregnancies are discussed in terms of intended or unintended. However, women’s attitudes toward potential pregnancies are much more complex than just intending to be or not intending to be pregnant [ | PMC9883907 |
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Overview and hypotheses | weight gain | The current study examined if there is a relationship between DE and young women’s attitudes toward a potential pregnancy. Additionally, the study assessed if various portrayals of pregnancy on social media influence such attitudes. Specifically, we manipulated whether participants saw modified or unmodified images of pregnancy and measured their DE thoughts and behaviors as predictor variables. We measured the effects of the predictor variables on attitudes toward a potential pregnancy, self-efficacy about maintaining healthy eating habits during pregnancy, attitudes toward gestational weight gain, and current body image when considering a potential pregnancy.Based on previous literature, we predicted that young women with higher levels of DE (hypothesis 1), young women who viewed modified social media portrayals of pregnancy (hypothesis 2), and young women with higher levels of DE who viewed modified social media portrayals of pregnancy (hypothesis 3) would have more negative attitudes toward a potential pregnancy, have lower self-efficacy about maintaining healthy eating habits during pregnancy, have more negative attitudes toward gestational weight gain, and have lower current body image when considering a potential pregnancy. | PMC9883907 |
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Methods | PMC9883907 |
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Participants | Participants were recruited from psychology classes at Texas A&M University – Corpus Christi and through posts on social media. Only participants who are 18 years old or older, female, and college students were eligible to participate in the study. The initial sample consisted of 177 participants. Six participants were removed because they were male, two were removed for identifying as nonbinary, and two were removed for answering the attention check question incorrectly. Finally, as our goal was to examine younger women’s attitudes toward potential pregnancy and because previous literature considered women under 30 to be young women, 13 participants were removed because they were above the age of 30. The final sample consisted of 154 women. The majority of the participants were Hispanic (49.6%) or White (49%), heterosexual (70.9%), and moderate (22%) or liberal/very liberal (38.3%). Additionally, the majority of the participants were single (42.6%) or in a committed relationship (40.4%). Data was collected in March 2022. | PMC9883907 |
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Measures | PMC9883907 |
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Eating Attitudes Test-26 (EAT-26) | eating disorder | The Eating Attitudes Test-26 (EAT-26), developed from the original Eating Attitudes Test-40, is a three-part questionnaire that uses body mass index (BMI), scores from a 26-item questionnaire, and four behavioral assessment questions as a screening to identify whether people are at-risk of developing an eating disorder [ | PMC9883907 |
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Attitudes Toward Potential Pregnancy Scale (APPS) | The Attitude Toward Potential Pregnancy Scale (APPS) is a brief self-report questionnaire that was developed to measure women’s feelings toward a potential pregnancy and their efforts to either become pregnant or avoid pregnancy [ | PMC9883907 |
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Gestational Weight Gain Psychosocial Risk Assessment Tool | weight gain | The Weight-Related Behaviors Questionnaire (WRB-Q) is a validated measure used to assess pregnancy-related factors that affect weight gain and retention during and after pregnancy [ | PMC9883907 |
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Pregnancy photos | The social media app Instagram was used to find pictures that show portrayals of pregnancy in either modified or unmodified images. After reaching out to several women on Instagram asking if they would be willing to grant us permission to use their photos in our study, two women agreed. We used six pictures from each woman for a total of 12 images. Specifically, there were three modified images and three unmodified images of each woman. Modified pictures had visual evidence of editing due to particularly smooth, blemish-free skin and staged sets. Unmodified pictures showed natural skin, such as stretch-marks and discoloration in day-to-day environments. See Additional file | PMC9883907 |
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Procedure | eating-disorder | Participants were first presented with an informed consent before proceeding to the survey. All participants completed the full Eat-26 questionnaire. Next, participants were randomly assigned to view either six photos of the pregnant women that were highly modified or six photos of the pregnant women that were not highly modified. Participants were presented with one photo at a time and were able to click through the photos at their own pace. Then, all participants were given the Attitude Toward Potential Pregnancy Scale followed by the Gestational Weight Gain Risk Assessment Tool. The last step of the survey consisted of demographic questions. At the end of the survey, participants were presented with a link to an eating-disorder help and information website resource. | PMC9883907 |
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Results | weight gain, disordered eating and pregnancy portrayal, eating disorder | REGRESSION, REGRESSIONS | According to the guidelines of the EAT-26, 95 women (67.4%) had lower levels of DE, and 43 women (30.5%) had higher levels of DE and would qualify for a referral to an eating disorder specialist. A series of hierarchal regressions were used to test if the presence of DE and the presentation of either modified or unmodified social media portrayals of pregnancy significantly predicted young women’s attitudes toward potential pregnancy, perceived self-efficacy during pregnancy, attitudes toward gestational weight gain, and body image when considering a potential pregnancy. For each hierarchal regression, we entered in Step 1 pregnancy portrayal and centered versions (based on scale means) of DE thoughts and DE behaviors. In Step 2, we entered the two two-way interactions between pregnancy portrayal and DE thoughts and pregnancy portrayal and DE behaviors. The first regression examined the effects on attitudes toward potential pregnancy. No main effects or two-way interactions were observed.The second regression examined if DE and pregnancy portrayal significantly predicted young women’s perceived self-efficacy to have healthy eating habits throughout future pregnancy. There was a main effect for pregnancy portrayal, A third regression was performed to test if disordered eating and pregnancy portrayal predicted young women’s attitudes toward gestational weight gain. There was a main effect for DE thoughts, A fourth regression examined the influence of disordered eating and pregnancy portrayal on young women’s body image when considering a future pregnancy. There was a main effect for DE thoughts, | PMC9883907 |
Discussion | weight gain | This research examined how DE and social media portrayals of pregnancy influence young women’s attitudes toward a potential pregnancy, perceived self-efficacy about maintaining healthy eating habits throughout pregnancy, attitudes toward gestational weight gain, and pre-pregnancy body image. Specifically, we hypothesized that young women with higher levels of DE thoughts and/or behaviors would have more negative attitudes toward a potential pregnancy, have lower self-efficacy about maintaining healthy eating habits throughout pregnancy, have more negative attitudes toward gestational weight gain, and have lower body image when considering a potential pregnancy. Supporting our hypothesis, young women with higher levels of DE behaviors had lower perceived self-efficacy about maintaining healthy eating habits throughout pregnancy. Pregnancy can be a time of significant stress for women, and DE behaviors tend to worsen during periods of distress [Additionally, contrary to our hypothesis, we found that young women with higher levels of DE thoughts had more positive attitudes toward gestational weight gain. This is unexpected as we expected that women with significant preoccupations with food and eating would be less accepting of weight gain, even during pregnancy [In addition, supporting our hypothesis, young women with higher levels of DE thoughts had lower pre-pregnancy body image when considering a potential pregnancy. We predicted this effect because young women with higher levels of DE thoughts tend to have particularly negative weight satisfaction, even without considering a potential pregnancy [Given that modified pictures of pregnancy on social media can give women unrealistic expectations of what they should look like if they were to become pregnant [The third hypothesis stated that young women with higher levels of DE who viewed modified social media portrayals of pregnancy would have more negative attitudes toward a potential pregnancy, lower self-efficacy about maintaining healthy eating habits during pregnancy, more negative attitudes toward gestational weight gain, and lower current body image when considering a potential pregnancy than young women with low levels of DE who viewed unmodified social media portrayals of pregnancy. Our results found no support for the influence of DE and social media portrayal of pregnancy on young women’s attitudes toward a potential pregnancy. In fact, we found no other effects on women’s attitudes toward a potential pregnancy. It is possible that the lack of effects might be driven by the age of the women (Finally, this interaction was not significant for any of the other measures: self-efficacy, attitudes toward gestational weight gain, or current body image when considering a potential pregnancy. It is possible that there is no relationship between DE and social media portrayals of pregnancy. However, it is more likely that this relationship exists, but the manner in which we examined it, with a relatively short exposure to pregnancy portrayals in social media might not have had the substantial impact that we were expecting. It is more likely that continuous and prolonged exposure to the manner in which pregnancy is portrayed in social media relates to the development or maintenance of DE and its cumulative impact on self-efficacy about maintaining healthy eating habits during pregnancy, more negative attitudes toward gestational weight gain, and lower current body image when considering a potential pregnancy. Taken together, hypothesis 3 was not supported. | PMC9883907 |
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Limitations and future directions | weight gain | One limitation was the likely floor effect we observed regarding young women’s attitudes toward potential pregnancy. Young women from 18 to 30 years-old are less likely to desire or try to become pregnant, regardless of their level of DE, because they are focused on their education, starting their careers, or just waiting until they are older to have children [Another limitation that the study might have had is the images used to depict portrayals of pregnancy. We utilized the same two women for the modified and unmodified social media portrayals of pregnancy. We chose to use the same women for both categories to avoid any confounding factors using several different women. However, the two women that we used for the study were traditionally beautiful, and their unmodified pictures may not exhibit average looking pregnant women. Future research can use pictures of less traditionally attractive women so that there is more of a visual difference between the modified and unmodified pictures. Future research could also use pictures of different women for both categories instead of using the same women for both.Additionally, future research could measure the amount of time young women spend on social media and the duration young women for which they view each picture, especially portrayals of pregnancy. Due to the short amount of time participants were exposed to social media portrayals of pregnancy, there may not have been a strong enough effect to show significant results. Therefore, future research could examine if viewing modified social media portrayals of pregnancy for extended periods of time has a greater impact on young women’s attitudes toward a potential pregnancy and other related factors.Finally, given some of the unexpected findings, a more qualitative approach to this research could be utilized. Specifically, the relationship between possessing higher levels of DE thoughts and more positive attitudes toward gestational weight gain should be examined qualitatively. Using a qualitative analysis would allow women to share their exact feelings rather than relying on multiple choice questions with limited elaboration. A more extensive evaluation of young women’s attitudes toward potential pregnancy and body image can be used to ensure better outcomes for both mother and child [ | PMC9883907 |
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Conclusion | weight gain | This study examined the influence of DE and social media portrayals of pregnancy on young women’s attitudes toward a potential pregnancy, self-efficacy about maintaining healthy eating habits throughout pregnancy, attitudes toward gestational weight gain, and current body image when considering a potential pregnancy. Our findings illustrate that DE appears to impact women’s self-efficacy, attitudes toward gestational weight gain, and general satisfaction with current body image. These findings can be used by both mental and physical health practitioners to be aware of the risks of DE and know how to incorporate such problems into perinatal care. | PMC9883907 |
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Acknowledgements | We would like to thank Dr. Amy Houlihan and Dr. Steven Seidel who provided feedback throughout the research process. | PMC9883907 |
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Author contributions | AHG and YZ conceptualized the study. AHG conducted the literature review. AHG and YZ curated the data and conducted the statistical analysis. AHG wrote the first draft of the manuscript. Both authors reviewed and approved the final manuscript. | PMC9883907 |
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Funding | Not applicable. | PMC9883907 |
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Availability of data and materials | The datasets generated during and/or analyzed during the current study are not publicly available because informed consent provisions did not cover public data sharing but are available from the corresponding author on reasonable request. | PMC9883907 |
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Declarations | PMC9883907 |
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Ethics approval and consent to participate | This study was approved by the TAMU-CC Institutional Review Board (TAMU-CC-IRB-2022-0352). All participants were provided informed consent to participate and were informed that they could withdraw without consequence at any time during the study. All the experiments in the study were conducted in accordance to the relevant guidelines and regulations. | PMC9883907 |
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Consent for publication | Informed consent was obtained from the depicted pregnant women to use their photos in the study and in the publication. | PMC9883907 |
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Competing interests | The authors declare that they have no competing interests. | PMC9883907 |
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References | PMC9883907 |
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Keywords | diabetic nephropathy, renal injury, MR, renal damage, hypertension | HYPERTENSION, DIABETIC NEPHROPATHY | Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are recommended as first-line drugs for hypertension with diabetic nephropathy owing to their renoprotective effect; however, their effect beyond lowering blood pressure (BP) has not been confirmed. Recent studies have shown that aldosterone plays a key role in causing renal injury; therefore, it is likely that mineralocorticoid receptor (MR) blockers inhibit aldosterone-induced renal damage in different ways from ACE inhibitors and ARBs. Therefore, we investigated the mechanism of the effect of an MR blocker on reducing the urinary albumin-to-creatinine ratio (UACR) using data from a randomized, double-blind, placebo-controlled phase 3 study (ESAX-DN) of a new nonsteroidal MR blocker, esaxerenone. This This | PMC9899688 |
Introduction | MR, hypertension, hypertensive, diabetic nephropathy | HYPERTENSION, DIABETIC NEPHROPATHY | Renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), are recommended as first-line drugs for hypertensive patients with diabetic nephropathy mainly for their blood pressure (BP)-lowering effects [Esaxerenone is a new nonsteroidal MR blocker that has been approved in Japan for the treatment of hypertension and is now under development by Daiichi Sankyo Co., Ltd. for diabetic nephropathy [In statistics, this type of analysis into the mechanism of an agent is called “mediation analysis” and has been used in medical and psychological research [This | PMC9899688 |
Methods | The reporting of this | PMC9899688 |
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Study design and population | This was a In the ESAX-DN study, patients were randomized to either esaxerenone or placebo treatment for 52 weeks after a 4-week run-in period, continuing their treatment with RAS inhibitors at a constant dosage throughout the study. To minimize the risk of increasing serum potassium (K | PMC9899688 |
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Outcomes | albuminuria | ADVERSE EVENTS, SECONDARY, REMISSION | The primary endpoint of the ESAX-DN study was the proportion of patients with UACR remission at the end of treatment, and the key secondary endpoint was the percentage change in the UACR from baseline at the end of treatment. The changes in BP and creatinine levels and the rate of transition to overt albuminuria were also assessed. Safety endpoints included adverse events, serum KOf these outcomes, data for the percentage changes in the UACR from baseline to the end of treatment, changes in BP, and changes in eGFR were used in this | PMC9899688 |
Assessments | renal disease | RENAL DISEASE | The UACR, calculated from first morning urine samples, was measured during the run-in period and every 4 weeks up to week 52 during the subsequent treatment period. BP and eGFR were monitored every 2 weeks up to week 8 and every 4 weeks from week 12 to week 52 during the treatment period. The eGFR with the modification in diet in renal disease was calculated using the formula modified by the Japanese Society of Nephrology [ | PMC9899688 |
Clinical assumptions | albuminuria | Several mechanisms may explain the renoprotective effect of esaxerenone. First, esaxerenone primarily reduces BP, which then leads to a reduction in glomerular pressure, and it can also reduce urinary albumin excretion. Second, esaxerenone may directly affect renal function and may also affect urinary albumin excretion. In addition to these mechanisms, esaxerenone may have other effects on albuminuria suppression.Based on these clinical assumptions, we considered SBP and eGFR as mediators that reflect the changes in BP and renal function and assumed the following causal relationships between the variables in this analysis (Fig. Causal relationships between variables. The graph displays the assumptions about causal relationships between variables. If an arrow points away from X and toward Y, it indicates that X causally affects YThe values of SBP and eGFR change longitudinally during treatment. In addition, SBP and eGFR may affect UACR changes in different manners. Therefore, to incorporate the changes in SBP and eGFR during treatment, two types of mediator variables were considered: the cumulative average value of change from baseline up to the end of treatment and the achieved value of change from baseline to just before the end of treatment. The former assumes a cumulative effect, and the latter assumes an acute effect of mediator variables on the outcome. | PMC9899688 |
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Statistical analysis | To quantitatively investigate direct and indirect effects, we used the concepts of the “natural direct” effect and the “indirect effect” [Some strong assumptions are required to identify natural direct and indirect effects: (i) no unmeasured confounding of the exposure-outcome relationship; (ii) no unmeasured confounding of the outcome-mediator relationship; (iii) no unmeasured confounding of the exposure-mediator relationship; and (iv) no mediator-outcome confounder that is itself affected by the exposure. In randomized studies such as the ESAX-DN study, assumptions (i) and (iii) would hold because of the randomization of the treatment, but (ii) and (iv) would not necessarily hold and cannot be confirmed by the data.To overcome this problem with the assumptions, a methodology with multiple mediators was considered in this analysis. The confounder for the mediator-outcome relationship was considered the mediator, and the joint indirect effect of all mediators was estimated [To estimate the natural direct and indirect effects, we used the regression-based approach for single mediator and multiple mediator settings (details are shown in Supplementary Text In addition to the direct and indirect effects, the proportion of the mediated effect was calculated as (indirect effect/total effect) × 100 (%), which expresses how much of the total effect is mediated through mediators. The CIs for estimates were constructed based on the bootstrap method with 1000 replications.As in the ESAX-DN study, the log-transformed UACR was used in the analyses and back-transformed and expressed in the original scale in the results (i.e., the effect on UACR reduction was expressed as the geometric mean ratio to baseline, compared with placebo). All statistical analyses were performed using SAS System Release 9.4 (SAS Institute Japan Ltd., Tokyo, Japan). | PMC9899688 |
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Results | PMC9899688 |
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Patients | A total of 455 patients were randomized, but 6 patients were excluded from the full analysis set ( | PMC9899688 |
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Discussion | albuminuria, microalbuminuria, diabetic nephropathy, diabetic kidney disease | DIABETIC NEPHROPATHY, DIABETIC KIDNEY DISEASE | In this This There are various discussions in the literature about microalbuminuria changes as a surrogate endpoint of diabetic kidney disease [There are several methodologies that can directly handle multiple and/or time-dependent mediators [The current analysis has several limitations. This was a In conclusion, esaxerenone has a UACR-lowering effect beyond lowering BP and thus can be a treatment option for diabetic nephropathy in patients with albuminuria. | PMC9899688 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41440-022-01008-w. | PMC9899688 |
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Acknowledgements | The authors would like to thank all the people who participated in this study and the reviewers for their useful and helpful comments on our manuscript. We also thank Diane Williams, PhD, of Edanz ( | PMC9899688 |
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Author contributions | Conceptualization, investigation: all authors. Statistical plan and analysis: YO and MT. All authors agree with the final version of the manuscript, the publication in this journal, and to be held accountable for all aspects of the work. | PMC9899688 |
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Funding | The ESAX-DN study and this | PMC9899688 |
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Data availability | Deidentified individual participant data and applicable supporting clinical study documents may be available upon request at | PMC9899688 |
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Compliance with ethical standards | PMC9899688 |
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Conflict of interest | YO and TS are employees of Daiichi Sankyo Co., Ltd. SI, NK, KS, MN and TW have received personal fees from Daiichi Sankyo Co., Ltd., and MT has received consultant fees from Daiichi Sankyo Co., Ltd. NK, KS and MN have received grants/research funding from Daiichi Sankyo Co., Ltd. | PMC9899688 |
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References | PMC9899688 |
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1. Introduction | HIGH BLOOD PRESSURE | This article reports the results of Regular aerobic physical activity (PA) improves numerous cardiometabolic risk factors, including high blood pressure [Despite the established cardiometabolic health benefits of aerobic PA, only 27% to 40% of African American (AA) women meet national PA guidelines [Culturally tailored PA interventions (i.e., interventions designed to recognize and address the unique sociocultural, norms, societal expectations, and behaviors of the intended population [This paper reports the results of a randomized pilot trial evaluating | PMC9859082 |
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2. Materials and Methods | PMC9859082 |
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