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REFERENCES | PMC10292617 | |||
Background | swelling, pain | COMPLICATIONS | The aim of the present study was to evaluate postoperative effects of platelet-rich fibrin (PRF) in wound and bone healing, pain, swelling and periodontal complications outcomes after impacted third molars extraction. | PMC10499344 |
Material and Methods | pain, swelling, tooth | A prospective, randomized, split-mouth, double-blind clinical trial was conducted. PRF was placed within sockets following tooth removal and before suturing mucoperiosteal flap while no treatment was performed on control group’s sockets. Patients were evaluated considering bone volume which was obtained in the 90-day postoperative period. Other variables included trabecular thickness, trabecular distance and grey values, pain, swelling, and wound healing. A Wilcoxon test and a t-Student test were used at a 5% significance level and a Friedman test was used to multiple comparisons. | PMC10499344 | |
Results | Forty-four surgeries were performed in the present study. The patients’ mean age was 22.41 (± 2.75 years) and 72.73% were women. PRF was associated to increased trabecular thickness and bone volume means ( | PMC10499344 | ||
Introduction | swelling, pain | IMPACTED, COMPLICATIONS | Impacted third molars extraction are the most common surgical procedure in the clinical practices of Oral Maxillofacial Surgeons (Due to the release of growth factors, platelet concentrates have been used to improve the healing process and enhance bone repair (The purpose of this study was to evaluate the postoperative effects of platelet-rich fibrin (PRF) in bone healing, wound healing, pain, swelling and periodontal complications outcomes after impacted mandibular third molars extraction. | PMC10499344 |
Material and Methods | inferior alveolar nerve block, postoperative pain, swelling, allergy, kidney diseases, pain, infection, tooth, systemic endocrine disorders | CLOTS, SYSTEMIC DISEASE, CLOT, INFILTRATION, IMPACTION, DIABETES MELLITUS, RECRUITMENT, KIDNEY DISEASES, ALLERGY, INFECTION, SECONDARY, HYPERTENSION, OSTEOPOROSIS | To address the purpose of this research, the investigators designed and implemented a randomized, split-mouth, double-blind, clinical trial. The study protocol was reviewed and approved by the Local Research Ethics Committee, University of Pernambuco, Brazil (certificate #: 08330919.0.0000.5207) and registered on the (Brazilian registry of clinical trials (ReBEC) number: RBR-64vgjd. All patients gave their written informed consent before randomization. The study was conducted in accordance with the declaration of Helsinki and followed all the protocols of the Consolidated Standards of Reporting Trials Statement (
Flow diagram of the randomized clinical trial and the information about volunteer recruitment and follow up.- Patient SelectionTo be included in the study sample, patients had to fulfill the following criteria: 1) indication for impacted third molar extraction; 2) both third molars with same impaction pattern and fully developed roots; 3) adults aged between 18 and 35 years old; 4) the absence of systemic diseases such as hypertension, diabetes mellitus, systemic endocrine disorders, kidney diseases and osteoporosis; 5) the non-use of medication that could interfere with the outcomes of the procedure such as antibiotics, non-steroidal anti-inflammatory drugs or corticosteroids; 6) having no signs or symptoms of infection; 7) having symmetric third molars, and 8) coagulogram showing normal platelet count (150,000-400,000/mm³). Patients were excluded as study subjects if pregnant or breast-feeding, had history of allergy or contraindication to any of the medications used in the study, or were smokers. Besides, patients who did not participate in all phases of the study, and those who did not have the adjacent mandibular second molar were also excluded.- Study DesignA randomized, split-mouth, double-blind, clinical trial was conducted. On control group socket was sutured with the clot alone and in PRF group clots from two tubes were applied to the socket prior to the final suture. All the surgical procedures were performed by the same surgeon (E. D. R. R.).Randomization regarding the experimental and control sides was performed using a computer-generated randomization code (Microsoft Office Excel® 2010). The randomization data were only known to the surgeon. Patients, the clinician that performed all clinical evaluations (R. A. P. M), the radiologist (A. A. P) and the statistical expert (B. C. E. V.) were blinded to the randomization data until the final analysis of the experiment.Initially, ten patients underwent mandibular third molar extractions (20 extractions) in order to determine the sample size. The sample size was estimated considering the standard deviation of the mean differences in bone volume between the experimental and control groups (4.402 mm³) and the standard deviation [4.364]. The sample size was calculated considering an alpha level of 0.05, a test power of 80% and a 95% confidence interval. Based on this data, the estimated optimum sample was 16 patients.- Surgical TechniqueThe surgical procedures were performed under local anesthesia (buccal and lingual infiltration and inferior alveolar nerve block). An incision was made in the distal region of the gingival sulcus of the second molar; an oblique mesial side incision of this tooth was then made to create the mucoperiosteal flap. Osteotomy and tooth sectioning were done with rotary instruments under manual irrigation. The third molar was extracted, and the surgical wound was cleaned by irrigation with 0.9 % saline. All patients received instructions regarding their diet and oral hygiene.In then PRF group, clots from two tubes were applied to the socket prior to the final suture, whereas in the control group, the socket was sutured with with the clot alone. The flap was repositioned and sutured with 4-0 silk thread (Ethicon). The suture was removed one week after surgery.Postoperatively, we prescribed a 0.12% chlorhexidine digluconate mouthwash for 7 days (15ml/1min/q12hr). Paracetamol (acetaminophen) 750 mg was provided to participants experiencing pain (≥ 3 score) within 4 hours after surgery as a rescue drug and every 6h thereafter.- Clinical Assessment and OutcomesThe predictor variable was the treatment (experimental vs. placebo). Patients had both lower third molars extracted at the same surgical time, and each side was randomly allocated to: 1) the experimental group, in which the socket was filled with a PRF plug; and 2) the control group, in which no filling was received (the opposite side).Bone volume was the primary outcome variable. The secondary outcome variables were trabecular thickness, trabecular distance, greyscale, pain, swelling and wound healing. and probing pocket depth.Cone beam computed tomography (CBCT) was performed using the i-CAT Next Generation (Imaging Sciences International, Pennsylvania, USA) operating at 120 kVp, 18.5 mAs, field of view (FOV) of 6 x 16 cm and 0.25 mm voxel size. CBCT images of each patient were obtained three months after surgery (T3) and exported for evaluation in ImageJ/Fiji software (National Institutes of Health, Bethesda, MD, USA). All CBCT evaluations were performed by an oral and maxillofacial radiologist with 10 years of experience. The images were registered with the Registration/Rigid 3D tool. A cubic volume of interest (VOI) (4mm in height, 4mm in length, and 4mm in depth) was determined over the medullary bone at the base and center of the socket. The standardization of this VOI was achieved with the ROI Manager function of ImageJ/Fiji software. All images were then converted into eight bits and binarized using the "Moments” automatic binarization method (
CBCT obtained three months after surgery (T3). panoramic (A), axial (B), and parasagittal (C) reconstructions showing the bone repair of a L-PRF socket and panoramic (D), axial (E), and parasagittal (F) reconstructions showing the bone repair of control a socket (same patient).The postoperative pain assessment was performed by the visual analog scale (VAS) using a 100 mm scale ranging from 0 (no pain) to 10 (maximum imaginable pain). The patients were asked to indicate the intensity at 30 minutes and at 2, 4, 6, 8, 12, 16, 24, 48 and 72 hours after the surgery, in the postoperative period. The swelling was assessed by comparing the values of three facial lines: 1) the distance from the lateral corner of the eye to the gonial mandibular angle; 2) the distance from the lowest point of the tragus to the mouth commissure; and 3) the distance between the lowest point of the tragus to the pogonion (Fig.
Swelling measurements.- PRF protocolBlood samples were taken in 10-mL tubes without anticoagulant. The tubes were centrifuged at 2700 rpm (approximately 400 g) for 12 minutes in a Daiki DT4000 centrifuge according to the method described by Dohan - Data analysisData were expressed as the mean, standard deviation, minimum and maximum values. To assess data normality, we conducted a Shapiro-Wilks test. For the normally distributed postoperative times variables, a t-Student test for paired samples was used to compare PRF and control groups at different postoperative times. In contrast, for the data that were not normally distributed, the Wilcoxon test was performed. The data were statistically analyzed using SPSS v. 20.0 (IBM Corp., Armonk, NY) with a significance level of 5%. | PMC10499344 |
Results | ±, swelling, pain | A total of 61 patients were recruited for the study. Thirty-seven did not meet the eligibility criteria and 24 were selected for the intervention. Two patients did not return for the postoperative evaluations and were excluded from the study. Thus, the final sample was composed of 22 patients, as shown in the flow diagram (Fig. There were no statistically significant differences among demographic variables. Mean operative times of third molar surgery were 21.6 minutes (± 2.1) in the control group and 21.4 minutes (± 1.6) in the experimental group and it did not differ in more than 5 minutes between each side of the same patient. Regarding these operative times, there was no statistically significant differences between the different sides of the same patient.The PRF group showed significantly higher wound healing scores at the third day (2.23 - poor) when compared with the control group (1.73 - very poor) (The patients began to report pain four hours after surgery (Regardless of the group, swelling peak occurred 72h after surgery (Tomographic evaluation showed significantly higher trabecular thickness and bone volume in the experimental group (
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Comparison of mean Landry index values between L-PRF and control groups. | PMC10499344 | |||
Comparison of pain scores (VAS) between L-PRF and control groups at different postoperative times. | PMC10499344 | |||
Comparison of mean swelling values between L-PRF and control groups. | PMC10499344 | |||
Measurements of trabecular thickness, bone volume and gray scale. | PMC10499344 | |||
Discussion | postoperative pain, Pain, swelling, pain, trauma | HAND SWELLING, COMPLICATIONS, INFLAMMATORY RESPONSE | The purpose of this study was to evaluate the postoperative effects of PRF in bone healing, wound healing, pain, swelling and periodontal complications outcomes after impacted mandibular third molars extraction. We hypothesized that PRF would enhance bone repair and would modulate the inflammatory response. The specific aims of the present study were 1) to measure differences in bone volume, trabecular thickness and greyscale for the two different treatment groups and 2) to evaluate the efficiency of PRF in terms of swelling reduction, pain and wound healing improvement. The results indicated that the use of PRF in impacted third molar sockets after the extraction significantly improves bone healing on the 90-day postoperative evaluation.Third molar extraction is the most common procedure performed on the clinical routine of Oral Maxillofacial Surgeons (The healing process, swelling, and pain can be affected by several factors, such as surgeon experience, degree of trauma, patient age and gender, and third molar surgery operative time (In the analysis of the modified Landry Index (The application of platelet concentrates following third molar extraction has been described in the literature with promising results (In some clinical trials (Regarding postoperative swelling and pain, the PRF group showed earlier pain and swelling reduction during peak (72 h). This finding agrees with data reported in previous studies (In our study, no periodontal defects adjacent to the second molar were observed in either group. Ritto A previous study (The use of CBCT images enables the analysis of bone structure parameters usually performed in micro-CT or histology (When discussing the limitations of our study, we cannot exclude the possible effects of rescue medication intake on postoperative pain levels. In this study, the patients received oral and written instructions regarding the use of acetaminophen. Pain subjectivity is a complicating factor in the patient’s understanding in regards to the need to take a rescue medication in the postoperative period. Postoperative wound healing evaluation was performed using a modified Landry index (The use of PRF in impacted third molar sockets after the extraction significantly improves bone healing as it exhibits higher trabecular thickness and bone volume on the 90-day postoperative evaluation. PRF reduces postoperative pain and swelling and improves wound healing during the postoperative period. Besides, it does not affect the distal probing depth of the second molar on the 90th day of postoperative period.Ackcnowledgements This study was partly financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001. BV is grateful to the ‘Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)’.Authors contributions Éwerton Daniel Rocha Rodrigues, DDS, OMFS, MSc, PhD student: The conception of the study, Surgical Procedures, Text Conceptualization, Final Text Approval.
Andrea dos Anjos Pontual, DDS, PhD: Tomgraphic Analysis, Final Text Approval.
Rômulo Augusto de Paiva Macedo, DDS, OMFS, MSc: Evaluator, Text Conceptualization.
Eduarda Helena Leandro do Nascimento, DDS, MSc, PhD: Evaluator, Text Conceptualization.
Belmiro Cavalcante do Egito Vasconcelos, DDS, PhD, Professor, Chair of ostgraduate: Statistical expert, Final Text Approval.Ethics The study was submitted and approved by the Ethical Committee, under the IRB approval number 08330919.0.0000.5207, and registered on the Brazilian Clinical Trials Registry RBR-64vgjd (REBEC).Conflicts of interest None of the authors is exposed to conflicts of interests, financial or corporate affiliations within the past years.Funding None of the authors received any amount of money or products as funding for this study. | PMC10499344 |
Background and Aims: | NASH | With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. | PMC10521801 | |
Approach and Results: | Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR | PMC10521801 | ||
Conclusions: | The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.
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INTRODUCTION | NAFLD, NASH, noncirrhotic NASH, TNF-α | CHRONIC LIVER DISEASE | NASH is a progressive form of NAFLD, one of the most common chronic liver diseases worldwide.Therapies targeting different pathogenic pathways in NASH are under investigation including nuclear receptor agonists like farnesoid X receptor (FXR), antioxidants, anti-inflammatory agents, antifibrotic agents, and modulators of the TNF-α pathway, among others.There are no approved therapies globally for NASH, with many of the investigational agents studied to date either failing to meet histological end points or demonstrating limited efficacy.Tropifexor (TXR), a potent nonbile acid FXR agonist, has been shown to be highly efficacious in animal modelsCenicriviroc (CVC), a potent inhibitor of C-C chemokine receptor types 2/5 (CCR2/5), has demonstrated antifibrotic and anti-inflammatory properties in animal models.The purpose of this study was to assess the safety and efficacy of the TXR and CVC combination in patients with noncirrhotic NASH compared with respective monotherapies. | PMC10521801 |
METHODS | PMC10521801 | |||
Study design and treatments | ICH | TANDEM (NCT03517540) was a 48-week, phase 2b randomized, multicenter, double-blind study conducted between September 2018 (first patient, first visit) and October 2020 (last patient, last visit) in 65 centers across 17 countries. The study design of TANDEM has been reported in detailThe original study treatment duration was 48 weeks. A protocol amendment allowed treatment to continue for up to ~8 additional weeks for patients who were unable to attend the study site for the scheduled week 48 end-of-treatment (EOT) assessments, including EOT liver biopsy, due to COVID-19 pandemic-related restrictions, which included temporary closures of clinics. The study protocol and all amendments were reviewed by an Independent Ethics Committee or Institutional Review Board for each center, and the study was conducted according to the ICH E6 Guidelines for Good Clinical Practice that have their origin in the Declaration of Helsinki. All patients provided written informed consent before any study-specific procedures were performed. | PMC10521801 | |
Study population | liver impairment, fibrosis, NASH, hepatic decompensation, diabetes | AUTOIMMUNE LIVER DISEASE, FIBROSIS, CHRONIC LIVER DISEASE, DIABETES | Male and female patients aged ≥18 years (at the time of the screening visit) weighing between 50 and 200 kg were eligible to participate in the study. Other key inclusion criteria were (1) an adequate liver biopsy sample for evaluation by a central reader, (2) presence of NASH as demonstrated by histologic evidence, and (3) presence of fibrosis stages F2/F3 as demonstrated on a liver biopsy with evaluation by a central reader during the screening period (as per NASH clinical research network [CRN] staging criteria).Key exclusion criteria included (1) current or history of significant alcohol consumption for a period of >3 consecutive months within 1-year before screening (>20 g/d in females and >30 g/d in males), (2) uncontrolled diabetes [glycosylated hemoglobin (HbA1c) ≥9% at screening], (3) clinical evidence of hepatic decompensation or severe liver impairment, (4) previous diagnosis of other forms of chronic liver disease or a history of autoimmune liver disease, and (5) women of childbearing potential or pregnant/lactating women. | PMC10521801 |
Study end point | NASH, fibrosis, steatohepatitis | ADVERSE EVENTS, SECONDARY, FIBROSIS, STEATOHEPATITIS | The primary objective/end point of TANDEM was to evaluate the safety and tolerability of TXR plus CVC in patients with NASH and fibrosis (stages F2/F3) by monitoring adverse events (AEs), vital signs, and laboratory values during 48 weeks of treatment as compared with TXR and CVC monotherapy. This primary objective was chosen as this was the first study to investigate combined FXR agonism with CCR2/5 antagonism in patients with NASH. The secondary end points of this study were to evaluate the proportion of patients who had at least a 1-point improvement in fibrosis stage (NASH CRN) without worsening of steatohepatitis and the proportion of patients with resolution of steatohepatitis without worsening of fibrosis, after 48 weeks of treatment. Exploratory end points included were reported | PMC10521801 |
Study assessments | NAFLD, itch, sleep disturbance, (PGIS).Predose, liver damage, fibrosis, NASH, lobular inflammation, steatosis, steatohepatitis | LIVER DAMAGE, FIBROSIS, BLOOD, STEATOSIS, STEATOHEPATITIS | Safety assessments were performed to assess the occurrence of AEs, serious AEs (SAEs), AEs leading to study discontinuation or dose reduction, AEs of special interest (AESIs), changes in vital signs, and changes in laboratory data. AEs, SAEs, and vital signs were assessed at screening; baseline; weeks 2, 4, 6, 8, 12, 16, 24, 32, 40, and 48; and post-treatment follow-up at week 52.To assess treatment-induced changes, paired liver biopsies (baseline and EOT) were reviewed by a central pathologist (blinded to visits and treatment) to score fibrosis staging and grading of steatohepatitis features (steatosis, lobular inflammation, and hepatocyte ballooning). Real-time readings of liver biopsies were also performed at baseline to assess eligibility for entry into the study and after treatment completion. See Supplemental Information, The NAFLD activity score (NAS) was calculated according to the NASH CRN criteria,MRI-PDFF was performed optionally in a subset of patients to quantify HFF at screening. All MRI scans were performed locally and sent to the central MRI laboratory for evaluation. Anthropometric assessments included height and body weight.Blood samples and fasting blood samples were collected to assess liver biochemistry, which included ALT, aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and lipid panels (ie, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, free glycerol, and free fatty acids).A number of noninvasive tests were performed to assess liver damage and function. See Supplemental Information, Patient-reported outcomes included the visual analog scale (VAS) for itch, VAS for sleep disturbance due to itch, Patient Global Impression of change (PGIC; end of study [EOS] only), and Patient Global Impression of severity (PGIS).Predose and postdose PK plasma samples were collected at specified time intervals over the study duration (weeks 4, 8, 12, 24, and 48). See Supplemental Information, | PMC10521801 |
Statistical analysis | treatment-emergent adverse, fibrosis, steatohepatitis | FIBROSIS, SECONDARY, EVENTS, EVENTS, STEATOHEPATITIS | Summary tables are presented by treatment group and analysis visit (as applicable) using descriptive statistics. Continuous variables are summarized by arithmetic mean and SD unless otherwise stated. The number and percentage of patients in each category are presented for categorical variables for each treatment group and all patients (total).There were no prespecified hypotheses and statistical models in this study. The primary safety variables were analyzed descriptively using a summary table of absolute and relative frequencies, overall and by preferred term (for the occurrence of AEs, SAEs, and AEs leading to study discontinuation or dose reduction), and using a summary table of absolute and relative frequencies, overall and by type of AEs (for AESIs). Only treatment-emergent adverse events were considered for the analysis.Due to the nature of the primary objective, the assessment was made based on the whole safety profile and not on quantitatively formulated hypotheses for distinct parameters. Therefore, the sample size was based on the feasibility with respect to expected speed of enrollment and duration of the study.For power considerations, events with a true incidence of 30% and above are likely to be observed (almost 100% probability) in a group of 50 patients (size of each treatment group). Events with true incidences below 10% down to 3% are still very likely to be observed, while events with <50% probability are observed only if the true incidence is less than about 2.5%.For the secondary objectives, the difference in the proportion of patients on the different TXR plus CVC regimens who achieved at least a 1-point improvement in fibrosis stage and/or resolution of steatohepatitis at week 48 was compared with TXR and CVC monotherapy patients. Treatment differences between TXR + CVC combination therapy and monotherapy with TXR or CVC were evaluated using a Cochran-Mantel-Haenszel test that controlled for baseline fibrosis stage (F2/F3).For the PK analysis, dose-response and exposure-response relationships for TXR, CVC, and TXR + CVC combination therapy with key selected safety (eg, ALT and AST) and efficacy end points including biomarkers (eg, FGF19 and GGT) were explored. | PMC10521801 |
Post hoc digital pathology and artificial intelligence analyses of treatment-induced changes in steatosis, hepatocyte ballooning, and liver fibrosis | NASH, qSteatosis, steatosis | LIVER FIBROSIS, STEATOSIS | Unstained, formalin-fixed sections from paired liver biopsies (baseline and EOT) were examined using second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with computer-assisted analyses. The liver sections were de-paraffinized, and tissue scanning was performed on Genesis200 (a fully automated, stain-free multiphoton fluorescence imaging microscope) and analyzed using artificial intelligence (AI)-based algorithms (HistoIndex Pte. Ltd) to quantitatively assess qFibrosis, qSteatosis, and qBallooning, as described.To compare steatosis and liver fibrosis changes from baseline and after 48 weeks of treatment, as assessed by NASH CRN scoring and by AI digital quantitation (qSteatosis and qFibrosis), patients in the 4 treatment arms were categorized as Progressor, No Change, or Regressor ( | PMC10521801 |
RESULTS | PMC10521801 | |||
Patient disposition and baseline demographics | NAFLD, NASH, fibrosis | INSULIN RESISTANCE, LIVER FIBROSIS, FIBROSIS | Overall, 643 patients were screened for study inclusion, with 193 patients (30.0%) meeting the entry criteria for randomization. Of the 193 patients who were randomized to study treatment, 158 patients (81.9%) completed the study (Figure CONSORT flow diagram of participant disposition by treatment group. Baseline patient demographics and characteristics are displayed in Table Demographics and baseline characteristicsReal-time readings of liver biopsies were performed at baseline to assess eligibility for entry into the study.Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CRN, clinical research network; CVC, cenicriviroc; ELF, enhanced liver fibrosis; FIB-4, fibrosis-4; HOMA-IR, homeostatic model assessment for insulin resistance; N, number of patients in group; n, number of patients with outcome; NAS, NAFLD activity score; TXRBased on baseline liver biopsies and NASH CRN histological scoring, F3 fibrosis was present in 64.0%, 79.2%, 78.7%, and 62.5% of patients in the TXR | PMC10521801 |
Safety | pruritus | ADVERSE EVENT | Rates of AEs were similar across treatment groups. Overall, 85.5% of patients experienced at least 1 AE (Table Occurrence of AEs during the study and TEAEs with ≥10% incidence, by preferred term
Abbreviations: AE, adverse event; CVC, cenicriviroc; N, number of participants in group; n, number of participants with outcome; SAE, serious AE; TEAE, treatment-emergent AE; TXRThe proportion of patients who experienced pruritus was the highest in the TXROverall, 21 of 193 patients (10.9%) discontinued from study treatment due to an AE, with most discontinuations occurring in the TXRThe AEs that attributed to the most discontinuations from study treatment were pruritus [TXR | PMC10521801 |
Liver tests, hepatic fat fraction, and fibrosis markers | NAFLD fibrosis, liver stiffness, fibrosis | LIVER FIBROSIS, FIBROSIS | In the TXR and combination groups, a decrease in ALT (Figure Geometric mean percentage change from baseline (95% CI) up to week 48 in all groups and change in hepatic fat fraction at weeks 24 and 48. (A) Geometric mean percentage change (95% CI) in ALT; (B) geometric mean percentage change (95% CI) in AST; (C) geometric mean percentage change (95% CI) in GGT; (D) geometric mean percentage change from baseline in hepatic fat fraction; and (E) patients with at least a 30% reduction in hepatic fat fraction. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CVC, cenicriviroc; GGT, gamma-glutamyl transferase; HFF, hepatic fat fraction; n, number of patients in group; TXRThere were no consistent changes from baseline to week 48 for liver stiffness (via Fibroscan), enhanced liver fibrosis scores, fibrosis biomarker test scores, NAFLD fibrosis scores, or magnetic resonance elastography-derived liver stiffness from baseline to week 48 with any TXR-containing dose. At week 48, although there was a slight reduction in post-treatment mean fibrosis-4 (FIB-4) from baseline (change from baseline: −0.02) in the TXR | PMC10521801 |
Liver histology | NASH, fibrosis, steatohepatitis | FIBROSIS, STEATOHEPATITIS | At least a 1-point improvement in fibrosis stage was observed in 32.3% (10/31), 31.6% (12/38), 29.7% (11/37), and 32.5% (13/40) of patients in the TXRParticipants’ histological response at week 48 in all groups based on NASH CRN staging. (A) Proportion of patients with change in fibrosis stage and (B) proportion of patients with steatohepatitis resolution. Abbreviations: CRN, clinical research network; CVC, cenicriviroc; TXRThe proportion of patients with paired biopsy results at week 48 with at least 2-point improvement in fibrosis (NASH CRN staging) regardless of steatohepatitis status or without worsening of steatohepatitis at 48 weeks of treatment was considered not to be clinically meaningful (Supplemental Table S2, At week 48, no consistent changes in liver collagen morphometry were observed in combination treatment groups, with the highest response in the TXR | PMC10521801 |
Digital quantitation and AI analyses of treatment-induced changes in steatosis, ballooning, and liver fibrosis | NASH, steatosis, fibrosis | LIVER FIBROSIS, STEATOSIS, FIBROSIS | Paired liver biopsies from 144 patients (TXRChanges in steatosis and liver fibrosis as assessed by NASH CRN scoring and by digital quantification from baseline to week 48. (A) In-depth analyses of fibrosis changes in different zones of liver lobule demonstrated that TXRTreatment-induced fibrosis changes in different zones of liver lobules and colocalization analysis of steatosis and fibrosis changes from baseline to week 48. (A) Digital quantification of fibrosis dynamics as a percentage change of fibrosis area in different zones of the liver lobule. The periportal and pericentral areas are set at 100 µm from the portal tract and the central vein, respectively, and the region in between is the Zone 2 area. There were no notable changes in the number of ballooned hepatocytes from baseline to week 48 with any of the 4 treatment regimens, irrespective of whether patients had a high or low number of ballooned hepatocytes. (Supplemental Figure S5A, | PMC10521801 |
Lipid parameters, body weight, and HOMA-IR | Mean LDL cholesterol increased (Figure Change in lipid parameters and body weight up to week 48. (A) Geometric mean percentage change (95% CI) in LDL cholesterol; (B) geometric mean percentage change (95% CI) in HDL cholesterol; and (C) mean change from baseline (95% CI) in body weight up to week 48 in all groups. Abbreviations: CVC, cenicriviroc; TXRA reduction in body weight from baseline was evident with TXR-containing groups by week 4. By week 24, the following mean changes from baseline were reported: TXRMedian HOMA-IR scores at baseline ranged between 4.60 and 6.63 across treatment groups, with the highest baseline score in the TXR | PMC10521801 | ||
Patient-reported outcomes | sleep disturbance, itch | There were no differences in the VAS scores for itch intensity and sleep disturbance due to itch across treatment groups. For patients who responded to the global PGIS questionnaire, results at weeks 12, 24, and 48 were similar to those at baseline across all treatment groups; most patients rated their symptoms as very mild, mild, or moderate. In patients who responded to the PGIC questionnaire, most in the CVC and TXR | PMC10521801 | |
Pharmacokinetics | No marked difference was present in the TXR predose mean plasma concentration range for the TXRPlasma concentration ranges of CVC in pre- and postdose PK samples were comparable across each of the study arms (predose concentration range, 179–204 ng/mL for the CVC group, 160–198 ng/mL for the TXR | PMC10521801 | ||
DISCUSSION | nausea, fatigue, fibrosis, liver fibrosis stage, NASH, pruritus, steatosis | REGRESSION, STEATOSIS, PATHOLOGY, FIBROSIS | This study was a 48-week, randomized, double-blind, multicenter trial with the primary objective to evaluate the safety and tolerability of TXR + CVC in patients with NASH and fibrosis as compared with TXR and CVC monotherapy. The safety profiles of the combination therapies of TXROverall, pruritus, nausea, and fatigue were the most frequently experienced AEs, with the highest incidence of pruritus observed in the TXR monotherapy group and notably lower with TXRThere was a decrease in ALT, AST, and GGT in the TXR monotherapy and combination groups from baseline during the 48-week period, while in the CVC monotherapy group, no such reduction was observed. A similar decrease in ALT from baseline with TXR was observed in the FLIGHT-FXR study.Although the observed fibrosis improvement was in the same range as in other placebo-controlled monotherapy studies with CVC or TXR,Although we did not see synergistic efficacy with these therapies when used in combination, this does not exclude such an effect in other combinations. As the effects of CVC on metabolic components of NASH are thought to be limitedThe post hoc digital pathology and AI analyses provided useful mechanistic details in the evaluation of NASH treatment with compounds of different mechanisms of action. TXR alone was shown to have greater impact in reducing steatosis than CVC monotherapy, consistent with TXR effects in reducing liver enzymes and HFF; the antifibrotic activity of TXR monotherapy was seen mainly in zone 1 and zone 2 of the liver lobule, while CVC showed antifibrotic effects uniformly in all 3 zones of the liver lobule. Although no significant difference in liver fibrosis stage was observed between the 4 treatment groups over the study period using conventional microscopy, digital quantitation analysis of fibrosis changes in different zones of the liver lobule revealed that the combination of TXR and CVC had an additive effect, achieving the greatest fibrosis reduction near steatosis in all 3 zones of the liver lobule, compared with each monotherapy group, with the TXRThe colocalization analyses assessing treatment-induced changes of fibrosis in relation to steatosis or hepatocyte ballooning, in the 4 treatment arms, confirmed the association that fibrosis regression occurs in cases with reduction of steatosis and hepatocyte ballooning, as described.The treatment effect on changes in lipid levels related to TXR treatment was apparent by week 4, near maximum by week 12, and with little change thereafter. This was similar to the stabilization of changes in lipid levels after week 12 in the FLIGHT-FXR study.PK data from this study confirm a similar predose exposure between TXRLimitations of this study include a small number of patients, limiting the power to address histological change, with the COVID-19 pandemic effect further decreasing effective sample size, and leading to missed visits and central laboratory assessments. | PMC10521801 |
CONCLUSIONS | TXR monotherapy showed sustained decrease in ALT and body weight, but there was no substantial incremental efficacy with the combination of TXR and CVC either on ALT or body weight reduction nor in histological end points when compared with the monotherapy arms. The TANDEM study demonstrated that the safety profile of this combination therapy (TXR + CVC) was similar to that of each of the monotherapies. There were no new safety signals compared with those already reported in monotherapy studies. | PMC10521801 | ||
Supplementary Material | PMC10521801 | |||
DATA AVAILABILITY | Trial information can be found at NCT03517540, ClinicalTrials.gov. | PMC10521801 | ||
AUTHOR CONTRIBUTIONS | Lazas | All authors were involved in the preparation and critical review of the manuscript and approved the final version for submission. All authors were involved in the interpretation of data in the manuscript. All authors agreed to be accountable for all aspects of the work and attest to the accuracy and integrity of the work. Acquisition of clinical data and investigators in the clinical study: Quentin M. Anstee, Kathryn J. Lucas, Sven Francque, Manal F. Abdelmalek, Arun J. Sanyal, Vlad Ratziu, Adrian C. Gadano, Michael Charlton, Edward Mena, Jörn M. Schattenberg, Mazen Noureddin, Donald Lazas, George B.B. Goh, Shiv Kumar Sarin, and Yusuf Yilmaz. Digital data analyses and interpretation: Elaine Chng and Nikolai V. Naoumov. Conception, design, and/or statistical/data analysis, and/or clinical conduct of the trial: Mary Rinella, Rohit Loomba, Miljen Martic, Rowan Stringer, Jossy Kochuparampil, Li Chen, Gerardo Rodriguez-Araujo, Nikolai V. Naoumov, Clifford Brass, and Marcos C. Pedrosa. | PMC10521801 | |
ACKNOWLEDGMENTS | The authors thank Nicola Harris (Novartis Pharmaceuticals UK Ltd, London, UK), Philip O’Gorman, PhD (Novartis Ireland Ltd, Dublin, Ireland), and Aruna Meka, PhD (Novartis Healthcare Pvt Ltd, Hyderabad, India) for providing medical writing support and assistance, which was funded by Novartis Pharma AG, Basel, Switzerland, in accordance with the Good Publication Practice (GPP 2022) guidelines ( | PMC10521801 | ||
FUNDING INFORMATION | The study was funded by Novartis Pharma AG, Basel, Switzerland. The TANDEM study was funded by Novartis Pharma AG. Quentin M. Anstee is an NIHR senior investigator supported by the Newcastle NIHR Biomedical Research Center. | PMC10521801 | ||
CONFLICTS OF INTEREST | Nordisk, Target-Pharma, Nordisk, and Terns., NASH, Nordisk, and Promethera. | RTI, RESOLUTION | Quentin M. Anstee, on behalf of Newcastle University, consults for Alimentiv, Akero, AstraZeneca, Axcella, 89 Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GlaxoSmithKline, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Pharmanest, Prosciento, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns. He received grants from AstraZeneca, Boehringer Ingelheim, and Intercept. He is on the speakers’ bureau for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare. He receives royalties from Elsevier. He is Coordinator of the EU-IMI-2 LITMUS consortium, which is funded by the EU Horizon 2020 programme and EFPIA. Sven Francque consults for, is on the speakers’ bureau for, and received grants from Genfit, Gilead, Janssen, Inventiva, and MSD. He consults for and is on the speakers’ bureau for Abbvie, Allergan, Bayer, Eisai, Intercept, Novo Nordisk, and Promethera. He consults for and received grants from Astellas and Roche. He consults for Actelion, Aelin Therapeutics, AgomAb, Aligos Therapeutics, AstraZeneca, BMS, Boheringer Ingelheim, CSL Behring, Coherus, Echosens, Enyo, Galapagos, Galmed, Genentech, Intercept, Julius Clinical, Madrigal, Medimmune, NGM Bio, and Novartis. He received grants from Falk Pharma, GlympseBio, and Pfizer. He holds a senior clinical investigator fellowship from the Research Foundation Flanders (FWO) (1802154N). Manal F. Abdelmalek consults for, advises, and received grants from Hanmi, Inventiva, and Novo Nordisk. She advises and received grants from Madrigal, BMS, and NGM Bio. She advises SonicIncytes, 89 Bio, Merck, and Theratechnologies. She is on the speakers’ bureau for Clinical Care Options, Fishawack, Medscape, Terra Firma, and CLDF. She received grants from Allergan, Boeringher-Ingelheim, Celegene, Durect, Enanta, Enyo, Galmed, Genetech, Gilead, Poxel, Target NASH, and Viking. Her institution received grants from 89 Bio, Enyo, Enanta, Durect, Celegene, Poxel, Genfit, Gilead, Genentech, Novartis, Novo Nordisk, Hanmi, Inventiva, BMS, Boehringer Ingelheim, Intercept, and Novo Nordisk. Arun J. Sanyal owns stock and consults for Genfit and Hemoshear. He consults for and received grants from Boehringer Ingelheim, Lilly, Novo Nordisk, Fractyl, Siemens, Madrigal, Inventiva, and Echosense-Sandhill. He consults for Intercept, Immuron, Pfizer, Salix, Sanofi, Sequana, Terns, Albireo, Jannsen, Poxel, 89 Bio, Astrazeneca, NGM Bio, Amgen, Afimmune, Bristol Myers Squibb, Regeneron, Gilead Galectin, Genentech, Glympse, Birdrock, Blade, Target-Pharma Teva, Artham, Salix, Alnylam, Roche, Chemomab, Covance, Conatus, Cumberland, Merck, Prosciento, Syntolgic, Surrozen, Histoindex, Malinckrodt, Nitto Denko, Nordic Biosciences, Novartis, Nimbus, Tobira, Valeant, Zafgen, Zydus, and Path AI. He owns stock in and consults for Exhalez, Galmed, and Takeda. He received grants from Second Genome, Cymabay, and Labcorp. He owns stock in Akarna, Durect, Indalo, Inversago, NorthSea, Tiziana, and Rivus. His institution has received grants from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, AstraZeneca, Malinckrodt, Cumberland, and Novartis. He receives royalties from Up-To-Date and Elsevier. He is president of Sanyal Bio. Vlad Ratziu consults and received grants from Intercept. He consults for Boehringer Ingelheim, Novo Nordisk, Sagimet, Terns, NGM Bio, Pfizer, North Sea, Madrigal, Enyo, and Poxel. He received grants from Gilead. Adrian C. Gadano is a national coordinator for Novo Nordisk. He is a principal investigator for BMS, Novo Nordisk, GSK. Michael Charlton consults for, advises, and received grants from Gilead. He consults for and received grants from Novartis. He consults for AbbVie, Intercept, Terns, Madrigal, Metacrine, Enterome, Sagmiet, North Sea, NGM Bio, Pfizer, and Merck. He received grants from Novartis, Conatus, and Galectin. Rohit Loomba consults for Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals, and Viking Therapeutics. His institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is the co-founder of LipoNexus Inc. Edward Mena consults for and is on the speakers’ bureau for Gilead, AbbVie, Eisai, and Salix. He is on the speakers’ bureau for Intercept. Jörn M. Schattenberg consults for, is on the speakers’ bureau for, and received grants from Boehringer Ingelheim. He consults for and is on the speakers’ bureau for Novo Nordisk and Madrigal. He consults for and received grants from Gilead Sciences and Siemens Healthcare GmbH. He consults for Apollo Endosurgery, Albireo, BMS, AGED diagnostics, Bayer, GSK, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, MSD, Northsea Therapeutics, Novartis, Pfizer, Roche, and Sanofi. He is on the speakers’ bureau for Echosens, MedPublico GmbH, and Histoindex. He received grants from Nordic Biosciences. Mazen Noureddin consults for, advises, and received grants from BMS, Gilead, Novo Nordisk, and Terns. He consults for and advises Altimmune, Boehringer Ingelheim, 89 Bio, Echosens, GSK, Merck, OWL, Pfizer, Roche, Siemens, and Takeda. He received grants from Allergan, Akero, Galectin, Genfit, Conatus, Corcept, Enanta, Madrigal, Novartis, Shire, Viking, and Zydus. He owns stock in Anaetos, Rivus Pharma, CIMA, ChronWell, and Viking. George B.B. Goh consults for Gilead, Boehringer Ingelheim, and Ionis Pharmaceuticals. He is on the speakers’ bureau for Novo Nordisk and Echosens. Yusuf Yilmaz consults for Zydus and Novo Nordisk. He is on the speakers’ bureau for Echosens. Miljen Martic is employed by and owns stock in Novartis. Rowan Stringer is employed by and owns stock in Novartis. Jossy Kochuparampil owns stock in and is employed by Novartis. Li Chen owns stock in and is employed by Novartis. Gerardo Rodriguez-Araujo owns stock in and is employed by AbbVie. Elaine Chng is employed by Histoindex. Nikolai V. Naoumov owns stock in and was employed by Novartis. He advises Histoindex. Clifford Brass owns stock in, was employed by, and owns intellectual property rights with Novartis. He owns stock in Merck. He is a Scientific Advisory Board member of EU-IMI 2 LITMUS consortium. Marcos C. Pedrosa owns stock, was employed by, and consults for Novartis. The remaining authors have no conflicts to report.
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, | PMC10521801 |
REFERENCES | PMC10521801 | |||
1. Introduction | RBD | CORONAVIRUS, GILBERT | Current address: Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37203, USA.Current address: Sanofi Vaccines R&D, 1541 Avenue Marcel Mérieux, 69280 Marcy l’Etoile, France.The Members of the Immune Assays; Moderna, Inc.; CoVPN/COVE; and USG/CoVPN Biostatistics Teams are listed in the The COVE trial randomized participants to receive two doses of mRNA-1273 vaccine or placebo on Days 1 and 29 (D1, D29). Anti-SARS-CoV-2 Spike IgG binding antibodies (bAbs), anti-receptor binding domain IgG bAbs, 50% inhibitory dilution neutralizing antibody (nAb) titers, and 80% inhibitory dilution nAb titers were measured at D29 and D57. We assessed these markers as correlates of protection (CoPs) against COVID-19 using stochastic interventional vaccine efficacy (SVE) analysis and principal surrogate (PS) analysis, frameworks not used in our previous COVE immune correlates analyses. By SVE analysis, hypothetical shifts of the D57 Spike IgG distribution from a geometric mean concentration (GMC) of 2737 binding antibody units (BAU)/mL (estimated vaccine efficacy (VE): 92.9% (95% CI: 91.7%, 93.9%)) to 274 BAU/mL or to 27,368 BAU/mL resulted in an overall estimated VE of 84.2% (79.0%, 88.1%) and 97.6% (97.4%, 97.7%), respectively. By binary marker PS analysis of Low and High subgroups (cut-point: 2094 BAU/mL), the ignorance interval (IGI) and estimated uncertainty interval (EUI) for VE were [85%, 90%] and (78%, 93%) for Low compared to [95%, 96%] and (92%, 97%) for High. By continuous marker PS analysis, the IGI and 95% EUI for VE at the 2.5th percentile (519.4 BAU/mL) vs. at the 97.5th percentile (9262.9 BAU/mL) of D57 Spike IgG concentration were [92.6%, 93.4%] and (89.2%, 95.7%) vs. [94.3%, 94.6%] and (89.7%, 97.0%). Results were similar for other D29 and D57 markers. Thus, the SVE and PS analyses additionally support all four markers at both time points as CoPs. In the coronavirus efficacy (COVE) phase 3 clinical trial of the mRNA-1273 COVID-19 vaccine, participants were randomized 1:1 to receive mRNA-1273 vaccine (In Gilbert et al. [Here, we report the results from additional CoP analyses of the COVE trial, completing the suite of pre-specified blinded-phase immune correlates analyses of the D29 and D57 antibody markers and COVID-19. Specifically, we evaluated each of the four markers, Spike IgG, RBD IgG, nAb-ID50, and nAb-ID80, measured at D29 or D57, as a CoP against COVID-19 defined using two additional causal inference frameworks for CoP assessment as specified in the master protocol SAP: the stochastic interventional vaccine efficacy (SVE) framework and principal surrogate (PS) framework (within the principal stratification framework of causal inference [ | PMC10612023 |
2. Materials and Methods | PMC10612023 | |||
2.1. COVE Trial and Study Endpoint | COVID-19 disease | SARS-COV-2 INFECTION | The COVE trial (NCT04470427), conducted in the United States, enrolled 30,420 adults age 18 and over at appreciable risk of SARS-CoV-2 infection and/or high risk of severe COVID-19 disease and randomly assigned them in a 1:1 ratio to receive either vaccine or placebo [ | PMC10612023 |
2.2. Ethics Statement | All study participants provided written informed consent before enrollment and the protocol and consent forms were approved by the central institutional review board. | PMC10612023 | ||
2.3. Case-Cohort Sets Included in the Correlates Analyses | A case-cohort sampling design [ | PMC10612023 | ||
2.4. Pseudovirus Neutralizing Antibody Assay | Serum nAb activity against SARS-CoV-2 was measured in a validated assay utilizing lentiviral vector pseudotyped with full-length Spike of the D614G strain NC_045512.2 [ | PMC10612023 | ||
2.5. Binding Antibody Assay | RBD | Serum IgG bAbs against Spike and RBD were measured using a validated solid-phase electrochemiluminescence S-binding IgG immunoassay [ | PMC10612023 | |
2.6. Stochastic Interventional VE | For each antibody marker, measured levels were hypothetically shifted along a grid, (−1.0, −0.8, −0.6, −0.4, −0.2, 0, 0.2, 0.4, 0.6, 0.8, 1.0), on the log | PMC10612023 | ||
2.8. Continuous Marker Principal Surrogate Evaluation | Gilbert [ | For each antibody marker measured on a continuous scale, the methods of Huang, Zhuang, and Gilbert [ | PMC10612023 | |
3. Results | PMC10612023 | |||
3.1. Stochastic Interventional VE Analysis Supports Each of the Four Antibody Markers as a Correlate of Protection | For a given immune marker measured at a post-vaccination time point, SVE analysis [Similar results were obtained for the D29 binding antibody markers ( | PMC10612023 | ||
3.2. Binary Principal Surrogate Analysis Supports Each of the Four Antibody Markers as a Correlate of Protection | NEH | For a given immune marker measured at a post-vaccination time point, PS analysis estimates VE for each of two or many subgroups defined by a participant’s value of the immune marker if assigned to the vaccine arm (observable in vaccine recipients and a counterfactual in placebo recipients). PS analysis was applied under the assumption that vaccination does not cause an increased risk of COVID-19 prior to the time of immune marker measurement (i.e., the NEH assumption) [ | PMC10612023 | |
3.3. Continuous Principal Surrogate Analysis Supports Each of the Four Antibody Markers as a Correlate of Protection | GILBERT | Second, the PS method of Huang, Zhuang, and Gilbert [As a comparison, in | PMC10612023 | |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10612023 | ||
Author Contributions | C.H. | CORONAVIRUS | Y.H., N.S.H., B.B., D.B., D.C.M., A.B.M., Y.F., H.E.J., D.F., R.O.D., R.A.K. and P.B.G. conceptualized the study. Y.H., N.S.H., B.B. and P.B.G. developed methodology used in the study. Y.H., N.S.H., B.B., D.B., Y.F., W.D., H.Z., Y.L., C.Y. and P.B.G. curated the data. Y.H., N.S.H., B.B., D.B., Y.F., Y.L., C.Y., A.K., M.C. and P.B.G. conducted the analyses. Y.H., N.S.H., B.B., D.B., D.C.M., A.B.M., Y.F., H.E.J., K.M., L.J., B.F., B.C.L., S.O., C.M., A.E., M.S.-K., Y.L., C.Y., J.M., H.M.E.S., L.R.B., L.A.J., T.B.C., J.C., M.P.A., J.G.K., L.C., K.M.N., R.P., R.O.D., R.A.K. and P.B.G. contributed resources to the project. Y.H., N.S.H., B.B., Y.L., C.Y. and P.B.G. developed software used in the analyses. C.R.H., S.O., M.S.-K., C.H., R.O.D., R.A.K. and P.B.G. performed project administration. Y.H., N.S.H., B.B. and P.B.G. validated the analysis results. Y.H., N.S.H., B.B., L.N.C. and P.B.G. wrote the original draft. The Immune Assays Team performed the binding antibody and neutralizing antibody experiments. The Moderna Inc. team curated the data and contributed resources to the project. The Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE) Team collected the clinical data in the study and contributed resources to the project. The U.S. government (USG)/CoVPN Biostatistics Teams curated the data, developed the software used in the analyses, conducted the analyses, and validated the results of the analyses. ICMJE guidelines for authorship have been adhered to. All authors have read and agreed to the published version of the manuscript. | PMC10612023 |
Institutional Review Board Statement | All relevant ethical guidelines were followed, and all necessary IRB and/or ethics committee approvals were obtained. The mRNA-1273-P301 study was conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Good Clinical Practice guidelines, and applicable government regulations. The Central Institutional Review Board approved the mRNA-1273-P301 protocol and the consent forms. Central IRB services for the mRNA-1273-P301 study were provided by Advarra, Inc., 6100 Merriweather Dr., Suite 600, Columbia, MD 21044. | PMC10612023 | ||
Informed Consent Statement | All participants provided written informed consent before enrollment. | PMC10612023 | ||
Data Availability Statement | Access to patient-level data and supporting clinical documents with qualified external researchers may be available upon request and subject to review. | PMC10612023 | ||
Conflicts of Interest | W.D., H.Z., J.M. and R.P. are employed by Moderna Inc. and have stock or stock options in Moderna Inc. | PMC10612023 | ||
References | NEH | GILBERT, SENSITIVITY | Stochastic interventional vaccine efficacy (SVE) estimates against COVID-19 with hypothetical shifts in geometric mean D57 antibody marker level. SVE, with 95% confidence intervals, for D57 (Binary principal surrogate vaccine efficacy (VE) against COVID-19 by D57 antibody marker greater than vs. less than or equal to the designated cut-point (median value). The black dot in each panel corresponds to the VE estimate for the relevant D57 antibody marker subgroup (Low or High) for (Continuous principal surrogate vaccine efficacy (VE) against COVID-19 by D57 marker level, with ignorance intervals (dark blue) and 95% estimated uncertainty intervals (light blue) under the No Early Harm (NEH) assumption shown for the sensitivity parameter β assumed to fall in the range [−log(4), 0]. Results are shown for (Four statistical frameworks for assessing an immune marker measured at a post-vaccination time point as an immune correlate of protection (CoP) against a clinical outcome from a vaccine efficacy trial, all of which were applied to the COVE trial.* This objective/definition attains in studies where all placebo recipients have the same value of the immune marker. This occurs in COVE, as baseline negative placebo recipients all have antibody levels to SARS-CoV-2 antigens that are below the assay detection limit. For VE trials where placebo recipients have variability in the immune marker (i.e., studies that enroll individuals previously infected with the pathogen), the objective/definition must be updated: to assess the VE that would be observed under a hypothetical intervention that assigns all participants to the vaccine arm and to a specific value of the marker, as opposed to assigning all participants to placebo and to a specific value of the marker.Principal surrogate correlates of vaccine efficacy (VE) results by Gilbert et al. method [* Sensitivity parameter settings were: None, β sensitivity parameters βPrincipal surrogate correlates of vaccine efficacy results by the Huang, Zhuang, and Gilbert method [CI, 95% confidence interval; EUI, 95% estimated uncertainty interval; IGI, ignorance interval. alpha = percentile of marker in vaccine recipients. | PMC10612023 |
ABSTRACT | ADVERSE REACTIONS, ADVERSE EVENTS, PREGNANCY COMPLICATIONS, HEPATITIS E, EVENTS | These authors contributed equally to this study.Supplemental data for this article can be accessed online at Special attention has been paid to Hepatitis E (HE) prophylaxis for pregnant women due to poor prognosis of HE in this population. We conducted a post-hoc analysis based on the randomized, double-blind, HE vaccine (Hecolin)-controlled phase 3 clinical trial of human papillomavirus (HPV) vaccine (Cecolin) conducted in China. Eligible healthy women aged 18–45 years were randomly assigned to receive three doses of Cecolin or Hecolin and were followed up for 66 months. All the pregnancy-related events throughout the study period were closely followed up. The incidences of adverse events, pregnancy complications, and adverse pregnancy outcomes were analysed based on the vaccine group, maternal age, and interval between vaccination and pregnancy onset. During the study period, 1263 Hecolin receivers and 1260 Cecolin receivers reported 1684 and 1660 pregnancies, respectively. The participants in the two vaccine groups showed similar maternal and neonatal safety profiles, regardless of maternal age. Among the 140 women who were inadvertently vaccinated during pregnancy, the incidences of adverse reactions had no statistical difference between the two groups (31.8% vs 35.1%, | PMC10026809 | |
KEYWORDS | PMC10026809 | |||
Introduction | HEV infection, viral hepatitis, Hepatitis E, infection, HEV infections, deaths | HEPATITIS E, VIRUS, VIRAL HEPATITIS, HEPATITIS E, INFECTION | Hepatitis E (HE) is a common viral hepatitis caused by the hepatitis E virus (HEV) infection. There are an estimated 20 million HEV infections worldwide every year, leading to approximately 3.3 million symptomatic cases and 44,000 deaths [A recombinant HE vaccine (Hecolin; Xiamen Innovax, Xiamen, China), which has been licensed in 2011 and 2020 in China and Pakistan, separately, is the world’s first and only vaccine to prevent HEV infection. It has been demonstrated with good safety and an efficacy of 100% within 12 months after the third dose in a large-scale, randomized, double-blind, placebo-controlled, phase 3 trial [Therefore, with a view to further investigation of the potential risk posed by HE vaccination during or shortly before pregnancy, we conducted a post-hoc analysis of pregnancy outcomes based on a large-scale phase 3 clinical trial of an | PMC10026809 |
Materials and methods | PMC10026809 | |||
Study population | This post-hoc analysis was based on a multi-centre, double-blind, randomized, and controlled phase 3 trial (ClinicalTrials.gov: NCT01735006) of an The trial was approved by the Independent Ethics Committee. Written informed consent was obtained from each participant, and the study was done in accordance with the principles of the Declaration of Helsinki, the standards of Good Clinical Practice, and Chinese regulatory requirements. | PMC10026809 | ||
Vaccines | The control HE vaccine (Hecolin, Xiamen Innovax, Xiamen, China) contains 30 μg of the purified HEV239 particulate antigen adsorbed to 0.8 mg aluminium hydroxide suspended in 0.5 mL buffered saline [ | PMC10026809 | ||
Safety monitoring | ADVERSE EVENTS, EVENTS, ADVERSE REACTIONS, MISCARRIAGE | Participants were observed for 30 minutes after each vaccination for the occurrence of any immediate reactions. All the participants were trained to record any solicited and unsolicited adverse events, medication administration, and other vaccinations occurred within 30 days after vaccination on the diary card distributed. Serious adverse events (SAEs) occurring within the 66-month study period were collected regularly by safety assessors. Adverse reactions, defined as adverse events related to vaccination, were judged by investigators with physician qualification according to the implementation rules, as described previously [All the participants in the trial should have negative urine pregnancy test results before each vaccination and were requested to avoid pregnancy within eight months after the first dose. Women with a positive test result should be suspended the vaccination and may continue two weeks after the end of pregnancy (delivery or miscarriage). All pregnancy events during the study period were recorded in detail through periodic telephone or in-person investigations. For pregnant women planning to deliver, regular telephone follow-up should be conducted at least once every three months. The last telephone survey should be conducted one month after the end of delivery. | PMC10026809 | |
Pregnancy outcomes and complications | abortion | Gestational age was measured from the first day of the last menstrual period (LMP) according to the international consensus. If LMP was unknown or unclear, gestational age would be reported based on ultrasound examination and an estimated LMP was also calculated. Pregnancy has three trimesters: first trimester (0–13 weeks), second trimester (14–26 weeks), and third trimester (27–40 weeks). The due date was the date of the first day of LMP plus 40 weeks (280 days), and maternal age was defined as the age at the time of the due date. Advanced maternal age was defined as 35 years or older. Pregnancy outcomes included termination and delivery. Elective termination was defined as an intentional abortion by an artificial procedure and was not considered as an adverse pregnancy outcome [ | PMC10026809 | |
Statistical analyses | ICH, abnormal foetal loss | ADVERSE EVENTS, PREGNANCY COMPLICATIONS, PREGNANCY COMPLICATIONS, REGRESSION, EVENTS, COMPLICATIONS | All statistical comparisons were made between the HE vaccine group and the HPV vaccine group using Student’s T-test, Chi-Squared test, Fisher’s exact test, Wilcoxon test, or Cochran-Mantel-Haenszel test.Characteristics of women who became pregnant and their pregnancy outcomes and complications were displayed. Women who inadvertently received HE vaccine during pregnancy were matched in a 1:2 ratio to those HE vaccinees who were nonpregnant throughout the study period. The matched factors included age at enrolment (no more than two years of difference), receiving the same HE vaccine doses and study site. The incidences of adverse events in participants vaccinated during pregnancy, as well as in matched nonpregnant women, were summarized.Pregnancy-related adverse events were divided into three parts: abnormal foetal loss outcomes, neonatal abnormality outcomes, and pregnancy complications in focus. To measure the impact of exposure time for pregnancy on adverse pregnancy outcomes and pregnancy complications, exposure types were classified as proximal and distal based on the interval between exposure and pregnancy. Proximal exposure was defined as vaccination during pregnancy or the onset of pregnancy within 90 days post any dose. Odds ratios with 95% confidence intervals were estimated with the use of a logistic regression model, with presence/absence of adverse pregnancy events considered as the dependent variable and the type of vaccine received and maternal age used as independent variables. The primary comparisons included: (1) pregnant women with any HE vaccine exposure vs those with any HPV vaccine exposure; (2) pregnant women with proximal HE vaccine exposure vs those with proximal HPV vaccine exposure; (3) pregnant women with distal HE vaccine exposure vs those with distal HPV vaccine exposure. In addition, comparison of pregnant women having proximal exposure with those having distal exposure was drawn specifically in the HE vaccine group, using the exposure types and maternal age as independent variables. To avoid masking the acute effects of vaccine, we conducted a sensitivity analysis based on defining proximal exposure as vaccination during pregnancy or the onset of pregnancy within 30 days post any dose. All analyses were performed using the generalized estimation equation (GEE) method to account for possible correlations between pregnancies of the same mother. The dependent variable was binomial (presence/absence of adverse pregnancy events), and hence the logit link function was used in the GEE model.Pregnancy complications and adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 20.0) developed by ICH. SAS version 9.4 was used for all the analyses. All reported | PMC10026809 |
Discussion | abnormal foetal loss | PREGNANCY COMPLICATION, HPV INFECTION, INFECTIONS TOE, EVENTS, INFECTION TOE | This post-hoc analysis showed that the HE vaccine did not have a negative effect on pregnancy relative to risks observed in HPV-vaccinated subjects. The incidences of adverse pregnancy outcomes were low and comparable between the HE vaccine receivers and HPV vaccine receivers. No potential risk was observed in vaccinated women of both the advanced or non-advanced maternal age. Additionally, there was no increased risk of abnormal foetal loss, neonatal abnormality, and pregnancy complication in women who received the HE vaccine during pregnancy or within 90 days pre-pregnancy compared with those who became pregnant at more than 90 days after vaccination. The vaccine was well tolerated during pregnancy and no vaccine-related SAE was reported.Since licensure in 2006, over 500 million doses of HPV vaccines have been distributed and 126 countries have introduced the HPV vaccine into their national immunization programmes [A large proportion of terminations were caused by elective terminations in our study, which may be closely associated with China’s birth control policy. During the first year of our study, only couples who were both from one-child families were allowed to have two children. Since November 2013, a selective two-child policy was available if either spouse was an only child, and a universal two-child policy was implemented by Chinese government after 2016 [There is increasing momentum to develop and implement maternal immunization to prevent specific infections to which pregnancy and newborns are susceptible. Theoretically, it is safe to receive an inactivated vaccine during pregnancy, whereas live vaccines should be contraindicated owing to the potential risk of infection to the foetus [As the only one commercialized HE vaccine around the world, Hecolin is of high priority for susceptible populations, including women of child-bearing age, and vaccinating women of child-bearing age has been indicated to be cost-effective from the societal perspective especially in epidemic regions [This post-hoc analysis was accompanied by a number of limitations. Firstly, the long-term effects of the vaccine on infants could not be analysed because the pregnancy events were followed only up to one month after delivery. Another limitation was the small number of women vaccinated during pregnancy. It is challenging to observe rare vaccine-related adverse outcomes based on such a limited sample size. A randomized, controlled clinical trial designed specifically for pregnant women would be the “golden rule” to rule out a meaningful difference in the percentage of adverse pregnancy outcomes. In addition, this phase 3 clinical trial was designed to evaluate the efficacy against HPV infection, therefore the antibody response specific to HEV after vaccination during pregnancy was not assessed and remained to be investigated.In conclusion, HE vaccination during or shortly before pregnancy is not associated with increased risks for both the pregnant women and pregnancy outcomes, but caution is needed until more adequate evidence is available. These data may be helpful to guide clinical practice in reducing undue concerns about the safety of vaccination during or shortly before pregnancy. | PMC10026809 |
Supplementary Material | PMC10026809 | |||
Supplemental Material | Click here for additional data file. | PMC10026809 | ||
Disclosure statement | Qiufen Zhang and Huirong Pan report being either current employees of Xiamen Innovax. No other potential conflicts of interest relevant to this article were reported. | PMC10026809 | ||
References | PMC10026809 | |||
Introduction | obesity, Obesity, CVD, CAD, diabetes | OBESITY, OBESITY, OBESE, CARDIOVASCULAR DISEASE, CVD, DISEASE, POLAND, HYPERTENSION, DISEASES, CAD, DIABETES | Edited by: Frederic Castinetti, Aix-Marseille Université, FranceReviewed by: Ewa Śliwicka, Poznan University of Physical Education, Poland; Hao Su, Beijing Sport University, China; Pei-Tzu Wu, Pacific University, United StatesCardiac adipose tissue (CAT) has become an important target for the reduction of disease risk. Supervised exercise programs have shown potential to "significantly" reduce CAT; however, the impact of different exercise modalities is not clear, and the relationships between CAT, physical activity (PA) levels and fitness (PFit) remain unknown. Therefore, the purpose of this study was to analyze the relationships between CAT, PA and PFit, and to explore the effects of different exercise modalities in a group of women with obesity. A total of 26 women (age: 23.41 ± 5.78 years-old) were enrolled in the cross-sectional study. PA, cardiorespiratory fitness, muscular strength, body composition and CAT were evaluated. The pilot intervention included 16 women randomized to a control (CON, n=5), high intensity interval training (HIIT, n = 5) and high-intensity circuit training (HICT, n=6) groups. Statistical analysis showed negative correlations between CAT and vigorous PA (VPA) (Obesity is a known risk factor for cardiovascular disease (CVD), diabetes, hypertension, and other diseases and it is characterized by excess adipose tissue (Under normal physiological conditions, CAT deposits protect the heart by secreting various molecules (e.g., anti-inflammatory and anti-atherogenic cytokines), however, excess CAT has been postulated as a distinct pathologic feature for CAD development (Various methods exist to estimate body fat (e.g., anthropometric measures, dual x-ray, magnetic resonance imaging, and radiation-exposing computed tomography) (Currently, the relationship between physical activity (PA) levels, physical health, and CAT accumulation is unknown (In this context, vigorous exercise has shown to improve anti-inflammatory and metabolic function, and cardiovascular health on a dose response fashion (The goal of this study was to analyze the relationships between PA, PFit, and CAT volume in obese women, and to pilot test the differential effects when comparing energy expenditure-matched high-intensity interval aerobic and resistance training interventions. | PMC10200876 |
Materials and methods | This study followed an observational cross-sectional design and was approved by the Institutional Review Board (ID: # 16-1208-4C). The reporting of observational studies (STROBE) recommendations was followed (Flow diagram.Assessments were performed in four sessions with a minimum of one day of rest between them (see Study design. | PMC10200876 | ||
Physical activity assessment | Participants were asked to wear an Actigraph GT3X accelerometer for seven days. The device was worn on the right hip and held in place | PMC10200876 | ||
Physical fitness assessment | PMC10200876 | |||
Dietary controls | PMC10200876 | |||
Cardiac adipose tissue assessment | PMC10200876 | |||
Pilot intervention study | The pilot intervention was registered at
| PMC10200876 | ||
Statistical analyses | Data are shown as mean and standard deviation (SD), unless otherwise stated. A Shapiro-Wilk test was performed to verify the normal distribution of the variables, where normality was assumed if p > 0.05. Associations between CAT volume and levels of PA and PFit were examined by Pearson’s and Spearman correlation analyses, depending on normal or non-normal distribution. Non-parametric Mann-Whitney U test and related samples Wilcoxon signed-rank test were utilized to analyze between groups and within group effects of the pilot intervention, respectively. The strength of the associations (rs) and effect sizes (r) were classified as ≤ 0.1 (very small/very weak), 0.1- 0.29 (small/weak), 0.3- 0.49 (moderate), 0.5- 0.69 (high/strong), 0.7- 0.89 (very high/very strong), and 0.9- 1 (perfect). The level of significance was set at | PMC10200876 | ||
Results | PMC10200876 | |||
Association study | Cardiac Adipose, Appendicular + Trunk | The mean age of the participants was 23.5 ±6.0 years of age. Data on PFit, PA, and diet are reported as means, standard deviations, minimum and maximum values as shown in Characteristics of the sample (n=26).CON, control group; HIIT, high-intensity interval training; HICT, high-intensity circuit training; BW, Body weight; BMI, Body Mass Index; %BF, % body fat; FM, Fat mass; LBM, Lean body mass; BMC, Bone Mineral Content; FFM, Free Fat Mass; TA-Fat ratio, (Appendicular + Trunk) to total Fat ratio; VAT, Visceral Adipose Tissue; SMM, Total Body Skeletal Muscle; CAT, Cardiac Adipose Tissue; 1RM-LP, 1 Max Rep Leg Press; 1RM-BP, 1 Rep Max Bench Press; rVO2, Relative VO2 peak; aVO2, Absolute VO2; LPA, Low Physical Activity; MPA, Moderate Physical Activity; VPA, Vigorous Physical Activity; MVPA, Moderate to Vigorous Physical Activity; %ST, percent sedentary time; SFA, Saturated Fatty Acids; MUFA, Monounsaturated Fatty Acids; PUFA, Polyunsaturated Fatty Acids; CHO, Carbohydrates.Association analyses between CAT, PA, PFit levels, and dietary macronutrients and sugars revealed moderate to high (0.3 – 0.7) significant associations (Analyses examining the PA data showed positive associations between all levels of activity and upper-body lean mass (LPA: Diet composition analyses revealed positive associations between daily energy intake and waist circumference ( | PMC10200876 | |
Pilot study | muscle mass, FM | Participants in the pilot study had a mean age of 23.7 ±7.6 years, a BMI of 32.7 ±1.7 kg/mThe nonparametric Wilcoxon test for related samples revealed significant changes in body composition and muscular health (muscle mass and function) with very strong effect sizes (0.83 – 0.90) only for the HICT group. Specifically, %BF and FM were significantly reduced after three weeks of intervention (Z = - 2.207, The Mann-Whitney U test revealed a significant increase of WtHR in the HIIT group compared to controls (Effects of the pilot interventions on body composition, muscular health, and cardiorespiratory fitness.CON, control group; HIIT, high-intensity interval training; HICT, high-intensity circuit training; BW, Body weight; BMI, Body Mass Index; WtH, Waist to Hip; %BF, % body fat; FM, Fat mass; LBM, Lean body mass; LM, Lean Mass; FFM, Free Fat Mass; SMM, Total Body Skeletal Muscle; 1RM-LP, 1 Max Rep Leg Press; 1RM-BP, 1 Rep Max Bench Press; rVO*p < 0.05; ** p < 0.01.CON versus HIIT.HIIT versus HICT.CON versus HICT.Data reported as means and standard deviations.Baseline MR-derived CAT values (CON: 58.5 ± 1.2 mL; HIIT: 39.9 ± 1.6 mL; HICT: 68.7 ± 0.9 mL) and echocardiography-derived CAT values (CON: 5.9 ± 0.09 mm; HIIT: 4.2 ± 0.16 mm; HICT: 5.1 ± 0.04 mm) were similar at baseline. The Mann-Whitney U test did not show significant differences between groups on change in CAT thickness (echocardiography) or volume (MR). Change in CAT. CON – control group; HIIT – high intensity interval training group; HICT – high intensity circuit training group; CAT (mm) – cardiac adipose tissue derived from echocardiography analysis; CAT (mL) – cardiac adipose tissue derived from magnetic resonance analysis. Data reported as means and standard error of mean.Magnetic resonance images representing pre- to post-intervention changes in cardiac fat of three participants. Close-up of the cardiac fat for a single subject in: | PMC10200876 | |
Discussion | obesity, FM | OBESITY, VIRUS | Overall, this study revealed that all types of PA are negatively associated with relative whole-body and lower-body fatness. Furthermore, this is the first study to reveal a significant negative link between CAT and VPA in women with obesity. In this study, only HICT showed significantly positive effects in body fat and lean mass content (i.e. %BF, WC, FM, LBM, FFM, lower-extremity LBM) and muscular strength after just three weeks of training. Since this is an exploratory study, larger samples are required to detect differences between groups (HIIT Studies in activity-related behaviors have revealed strong relationships between reduced PA, increased sedentary time and obesity (To the best of our knowledge, no other studies have reported nor analyzed the associations between CAT and VPA levels. Analysis of the body composition revealed positive associations of CAT with WC and VAT that is consistent with the literature (Regarding diet’s composition, participants diet was not different from current guidelines for Americans, except for sugars 21.3% which were above the 10% recommended (Our data revealed negative correlations between consumption of both sugar and carbohydrates and MPA and LPA levels. Other studies have linked low levels of PA and increased sedentary behaviors (e.g., increased TV, video and computer time) with high sugar intake and other unhealthy dietary habits (e.g., poor vegetable and fruit consumption) (There is considerable interest in learning how to prevent CAT accumulation. Recent studies in the effectiveness of exercise interventions, have shown CAT reduction associated with improvements in FM or %BF (Our results emphasize the importance of the selection of an adequate exercise “dose” (i.e. frequency, intensity and time), mode (i.e. resistance, endurance), and format (i.e. traditional vs circuit format). Circuit training is a particularly well-liked exercise program style due to its ability to combine high-intensity resistance and aerobic interventions (This research is not without limitations. One important limitation is the sample size which limits the generalization of our results, so caution should be used when interpreting both CAT volume associations and the optimal exercise mode (HIIT versus HICT) to reduce CAT. The reason behind this was the interruption caused by COVID-19 (Corona virus) pandemic. Furthermore, in order to avoid the probability of committing type II error (given the small sample size) we did not perform Bonferroni correction; however, this might have increased the risk of a type I error linked to multiple comparisons. This exploratory research did not include Some important features strengthen this study. The research was designed following the criteria for cross-sectional and randomized control trials. The sample was homogeneous (women with obesity but otherwise healthy) and menstrual cycle was monitored to ensure all participants were evaluated during the same hormonal phase. In addition, samples on the pilot intervention (CON, HICT and HIIT) were equivalent at baseline. Another feature that strengthens this exploratory study is that the intensity prescribed in this program met the recommendations, and energy expenditure was monitored and matched in both HIIT and HICT; hence, allowing for realistic comparisons. Lastly, total CAT was measured | PMC10200876 |
Conclusions | obesity | OBESITY, CVD | All types of PA have a positive influence on whole-body and lower-body fat and muscle content. However, only VPA shows potential to significantly impact CAT volume. Moreover, short-term high-intensity exercise strategy in women with obesity shows promise, as three weeks of HICT induced positive changes in their body composition and muscular health. Future research is needed to explore vigorous intensity activity and high-intensity interval exercise interventions as tools for physical fitness optimization, CAT reduction and CVD risk management in women with obesity short- and long-term. | PMC10200876 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10200876 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Institutional Review Board (ID: # 16-1208-4C) at Southern Illinois University Edwardsville. The patients/participants provided their written informed consent to participate in this study. | PMC10200876 | ||
Author contributions | PD | MF-d-V and JK conceived and designed the research, and PW, BS, PD, and AG edited and revised the manuscript. BSS, PD, BS, AG, PW, JK and MF-d-V performed the experiments. MF-d-V, JP-R, JK and ST analyzed the data. MF-d-V, ST and JP-R interpreted the results of the experiments, MF-d-V, ST and JK prepared figures, and MF-d-V, ST, JP-R, BS and JK drafted the manuscript. MF-d-V, BSS, PD, BS, AG, JP-R, PW, and JK approved the final version of the manuscript. | PMC10200876 | |
Acknowledgments | The authors want to acknowledge all participants for their time and effort. We would also like to thank the undergraduate research assistants and the team at the Writing Center in Southern Illinois University Edwardsville for their help. | PMC10200876 | ||
Conflict of interest | Author BSS was employed by Heartland Medical Research, Inc.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10200876 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10200876 | ||
Supplementary material | cardiac adipose | The Supplementary Material for this article can be found online at: Individual changes of CAT by group. CON, control group; HIIT, high intensity interval training group; HICT, high intensity circuit training group; CAT (mm), cardiac adipose tissue derived from echocardiography analysis; CAT (mL), cardiac adipose tissue derived from magnetic resonance analysis.Click here for additional data file.Click here for additional data file.Click here for additional data file. | PMC10200876 | |
References | PMC10200876 | |||
Background | balance-related behaviors | CHILDHOOD OBESITY, CURB | Widespread establishment of home-based healthy energy balance-related behaviors (EBRBs), like diet, physical activity, sedentary behavior, screen time, and sleep, among low-income preschool-aged children could curb the childhood obesity epidemic. We examined the effect of an 8-month multicomponent intervention on changes in EBRBs among preschool children enrolled in 12 Head Start centers. | PMC10029790 |
Methods | The Head Start (HS) centers were randomly assigned to one of three treatment arms: center-based intervention group (CBI), center-based plus home-based intervention group (CBI + HBI), or control. Before and following the intervention, parents of 3-year-olds enrolled in participating HS centers completed questionnaires about their child’s at-home EBRBs. Adult-facilitated physical activity (PA) was measured by an index based on questions assessing the child’s level of PA participation at home, with or facilitated by an adult. Fruit, vegetable, and added sugar intake were measured via a short food frequency questionnaire, and sleep time and screen time were measured using 7-day logs. A linear mixed effects model examined the intervention’s effect on post-intervention changes in PA, intake of fruit, vegetable, and added sugar, sleep time, and screen time from baseline to post-intervention. | PMC10029790 | ||
Results | A total of 325 parents participated in the study (CBI | PMC10029790 | ||
Conclusions | obesity | OBESITY | Parent engagement strengthened the improvement in parent-reported EBRBs at home in young children participating in an evidence-based obesity prevention program in a childcare setting. Future studies should investigate equity-related contextual factors that influence the impact of obesity prevention in health-disparity populations. | PMC10029790 |
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