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Statistical Analysis
death, bleeding, PAD, stroke, peripheral artery disease, CHF, CAD, nonadherence, diabetes
CHF, BLEEDING, PERIPHERAL ARTERY DISEASE, CONGESTIVE HEART FAILURE (CHF), CARDIOVASCULAR DISEASE, HYPERLIPIDEMIA, STROKE, PAD, SECONDARY, ATRIAL FIBRILLATION, HYPERTENSION, ASCVD, CORONARY ARTERY DISEASE, CAD, DIABETES
The statistical analysis plan was prespecified before conducting the analyses but after database lock. Baseline characteristics, medical history, and selected concomitant medications are presented separately for participants who took enteric-coated or uncoated aspirin by randomly assigned aspirin dose. Discrete variabl...
PMC10551818
Results
PMC10551818
Demographic Characteristics, Medication Use, and Medical History
Of 15 076 participants enrolled in the ADAPTABLE study, 10 678 (70.1%) reported the aspirin formulation used (median [IQR] age, 68.0 [61.3-73.7] years; 7285 [68.2%] men and 3393 [31.8%] women; 900 [8.4%] Black or African American, 8965 [84.0%] White, 482 [4.5%] other race (Asian, American Indian or Alaska Native, multi...
PMC10551818
Participant Demographic and Presenting Characteristics, Medical History, and Medications
bleeding, PAD, ICH, peripheral artery disease, CHF, COPD
BLEEDING, MYOCARDIAL INFARCTION, PERIPHERAL ARTERY DISEASE, CARDIOVASCULAR DISEASE, INTRACEREBRAL HEMORRHAGE, GI TRACT BLEED, CVD, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD, PAD, BLEEDING DISORDER, CONGESTIVE HEART FAILURE, CHF
Abbreviations: ARM, acid reducing medication; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CABG, coronary artery bypass graft; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; EHR, electronic health record; GI, gast...
PMC10551818
Diagram of Patient Flow in the Analysis
Participants were randomly assigned to aspirin dose but not to aspirin formulation, which was at the discretion of the participant. For several analyses, participants were grouped by aspirin formulation regardless of aspirin dose (shown at the bottom of the figure). Regardless of aspirin dose, there were 7366 total par...
PMC10551818
Effectiveness Outcomes
Within the enteric-coated aspirin cohort, the primary effectiveness end point occurred in 297 participants (cumulative incidence at median follow-up 6.6%) in the 81-mg dose group and 246 participants (7.2%) in the 325-mg dose group (adjusted hazard ratio [AHR], 1.13; 95% CI, 0.88-1.45) (
PMC10551818
Cumulative Incidence of Study End Points by Aspirin Formulation Type and Randomly Assigned Dose of Aspirin
MYOCARDIAL INFARCTION
Abbreviations: GI, gastrointestinal; MI, myocardial infarction.Cumulative incidence is reported at median follow-up, 26.2 months from randomization.Adjustment variables include age, sex, ethnicity, strata, race, prior aspirin use, P2Y
PMC10551818
Cumulative Incidence of the Primary End Point (All-Cause Death, Myocardial Infarction [MI], or Stroke) by Randomly Assigned Aspirin Dose (81 or 325 mg) and by Self-Selected Aspirin Formulation (Enteric-Coated or Uncoated) From Participant Self-Reported, Electronic Health Record, and Claims Data
AHR indicates adjusted hazard ratio.
PMC10551818
Safety Outcomes
bleeding
BLEEDING
Overall bleeding requiring blood product transfusion (major bleeding) was low in ADAPTABLE. Across the 4 cohorts, there was no significant interaction of major bleeding by aspirin dose or formulation (
PMC10551818
Cumulative Incidence of Bleeding Accounting for the Competing Risk of Death by Randomly Assigned Aspirin Dose (81 or 325 mg) and Self-Selected Aspirin Formulation (Enteric-Coated or Uncoated) From Participant Self-Reported, Electronic Health Record, and Claims Data
bleeding
BLEEDING
Major bleeding was defined as bleeding requiring blood product transfusion. AHR indicates adjusted hazard ratio.
PMC10551818
Sensitivity Analyses
death
EVENT
In a sensitivity analysis of time-varying self-reported aspirin dose, reflecting the association of aspirin dose at the time of the event, aspirin formulation, with or without covariate adjustment, did not modify the association of self-reported aspirin dose with the primary effectiveness outcome, all cause death, or t...
PMC10551818
Discussion
GI tract bleeding, bleeding
EVENTS, SECONDARY, ASCVD, BLEEDING
In this post hoc secondary analysis of ADAPTABLE, a large multicenter, pragmatic, randomized clinical trial, we evaluated the association of aspirin formulation (enteric-coated vs uncoated aspirin) with the effectiveness and safety of aspirin in secondary prevention of ASCVD. The results of this analysis did not show a...
PMC10551818
Limitations
bleeding, ASCVD
MINOR, BLEEDING, ASCVD
This study has limitations. First, formulation of aspirin was participant determined, and participants reported only at baseline, with only 70.1% of the participants reporting the formulation of the aspirin they were using. The determination of whether a participant took the reported medication or was adherent to it wa...
PMC10551818
Conclusions
bleeding, ASCVD
SECONDARY, ASCVD, BLEEDING
In this post hoc secondary analysis of data from the ADAPTABLE randomized clinical trial, there were no significant differences in the primary effectiveness or safety end points between enteric-coated aspirin and uncoated aspirin among participants with established ASCVD although a reduction in bleeding with enteric-co...
PMC10551818
Background/Objective
centre-involving diabetic macular oedema
PROLIFERATIVE DIABETIC RETINOPATHY (PDR)
The prokinetic levosulpiride elevates vasoinhibin levels in the vitreous of patients with proliferative diabetic retinopathy (PDR) suggesting clinical benefits due to the anti-vasopermeability and anti-angiogenic properties of vasoinhibin. We investigated the biological activity of levosulpiride in centre-involving dia...
PMC10858020
Patients/Methods
centre-involving
Prospective, randomized, double-blinded, dual-centre, phase 2 trial in patients with centre-involving DME orally treated with placebo (
PMC10858020
Results
Levosulpiride improved changes from baseline in best-corrected visual acuity (
PMC10858020
Conclusions
centre-involving
Oral levosulpiride for 8 weeks improved visual and structural outcomes in patients with centre-involving DME by mechanisms that may include intraocular upregulation of vasoinhibin and downregulation of VEGF and PlGF. Larger clinical trials evaluating long-term efficacy and safety are warranted.
PMC10858020
Subject terms
PMC10858020
Introduction
Diabetic retinopathy, centre-involving, visual impairment, microvascular complications, vasopermeability, vision loss, loss of vision, diabetes
LEAKAGE, DIABETIC GASTROPARESIS, DIABETIC RETINOPATHY, DIABETIC MACULAR OEDEMA, LOSS OF VISION, DIABETES
Diabetic retinopathy (DR) and diabetic macular oedema (DME) are microvascular complications causing visual impairment in diabetes. Leakage from retinal capillaries in DME produces the accumulation of extracellular fluid and proteins that alter the structure and function of the macula and may lead to permanent loss of v...
PMC10858020
Patients and methods
MAY, RETINA, DEL
This is a phase 2, prospective, double-blinded, randomized clinical trial conducted from May 2017 to November 2022 at two sites in Querétaro, México (Instituto Mexicano de Oftalmología and Instituto de la Retina del Bajío) and sponsored by the Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCYT, grants 24...
PMC10858020
DME study
PMC10858020
Protocol
hyperprolactinemia, Diabetic Retinopathy, glaucoma, centre-involving
DIABETIC RETINOPATHY, BLIND, GLAUCOMA, HYPERPROLACTINEMIA, TYPE 2 DIABETES, INTRAOCULAR PRESSURE
From 176 screened mestizo patients with type 2 diabetes, there were 55 eligible centre-involving DME participants (aged 40–69 years, best-corrected visual acuity (BCVA) between 58 to 16 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 4 m (20/16 to 20/100 Snellen equivalent), and central foveal thickness (...
PMC10858020
Primary endpoints
BCVA, OCT, and fluorescein angiography were assessed by certified examiners using standardised protocols as reported [
PMC10858020
Secondary endpoint
PRL levels in serum confirmed adherence to levosulpiride treatment (also monitored by counting drug tablet return) and were quantified using the IMMULITE 2000 XPi immunoassay system (Siemens, Munich, Germany). The intra-assay and inter-assay coefficients of variation were less than 1%.
PMC10858020
Safety assessment
ADVERSE EFFECTS
Medical history, physical examination, ocular pressure, vital signs (sitting systolic and diastolic blood pressure), and laboratory tests in blood (HbA1c and creatinine) evaluated the safety of the study medication (levosulpiride vs. placebo). The occurrence of adverse effects was also sought by nondirective questionin...
PMC10858020
PDR study
PMC10858020
Protocol
PDR, type 2 diabetes, hyperprolactinemia
HYPERPROLACTINEMIA, TYPE 2 DIABETES
Briefly, from 175 screened PDR mestizo patients with type 2 diabetes undergoing elective primary pars plana vitrectomy, 41 eligible patients signed the informed consent, and their blood was withdrawn to evaluate PRL, HbA1c, and creatinine levels. From these 41 patients, 2 were excluded due to basal hyperprolactinemia (...
PMC10858020
Primary endpoints
VEGF and PlGF were measured in the same vitreous sample by enzyme-linked immunosorbent assay (ELISA) using the Quantikine Human VEGF and PlGF kits (R&D System, Minneapolis, MN) performed according to the manufacturer’s instructions. The intra-assay and inter-assay coefficients of variation for VEGF were 5.4% and 7.3%, ...
PMC10858020
Secondary endpoint
PRL levels in serum at baseline and at vitrectomy were measured as indicated above.
PMC10858020
Statistics
GraphPad Prism Software Inc. version 6.01 was used. Statistical differences between two groups were determined by Student’s
PMC10858020
Results
PMC10858020
BCVA outcome
As early as 4 weeks after initiating treatment with levosulpiride, the mean longitudinal change in BCVA over baseline was significantly higher than after placebo (Fig. 
PMC10858020
Levosulpiride improved the change from baseline in visual and structural parameters.
Changes from baseline in best-corrected visual acuity (BCVA) (
PMC10858020
CFT and MMV outcomes
The overtime BCVA improvement with levosulpiride was paralleled by longitudinal upgrades in CFT and MMV. The mean CFT longitudinal change of study eyes declined relative to baseline at weeks 4 to 8 after levosulpiride vs. placebo and accounted for a mean loss of 46.6 μm at the end of treatment (Fig. 
PMC10858020
Overall visual and anatomic outcomes
RETINA
Finally, the overall change from baseline to week 8 of all primary endpoints (BCVA, CFT, MMV, OCT macular image, fundoscopy, and fluorescein angiography) was evaluated by six independent retina specialists blinded to treatment through a scale that ranged from −4 to +4, where −4 was highest worsening, 0 no change, and +...
PMC10858020
Levosulpiride improved the overall grading of primary endpoints.
Three examples of levosulpiride- (
PMC10858020
Safety
Somnolence, tachycardia, somnolence
ADVERSE EFFECTS, SIDE EFFECT
Only two DME patients reported adverse effects. One patient in the placebo group informed tachycardia 2 weeks after treatment and abandoned the study, whereas one levosulpiride case reported somnolence, which could relate to the study medication as it is a known side effect of levosulpiride. Somnolence occurred 6 weeks...
PMC10858020
Vitreous levels of VEGF and PlGF
PDR
The vitreous concentrations of VEGF and PlGF were significantly reduced in PDR patients treated with levosulpiride (Fig. 
PMC10858020
Levosulpiride reduced the vitreous levels of VEGF and PlGF by mechanisms that may involve the prolactin/vasoinhibin axis.
Vascular endothelial growth factor (VEGF) (
PMC10858020
Discussion
vascular retinopathies, centre-involving, diabetic, hyperprolactinemia, ocular complications, vision loss, gain of vision
HYPERPROLACTINEMIA, MACULAR OEDEMA, DIABETIC GASTROPARESIS, COMPLICATION
Levosulpiride is a prokinetic [The study was designed to assess the efficacy of levosulpiride in previously untreated DME patients with the caveat of deferring for the end of the study any other treatment. Accordingly, the protocol was short-termed (8 weeks) and carried out in DME patients with moderate vision loss (de...
PMC10858020
Summary
PMC10858020
What was known before
diabetic retinopathy, hyperprolactinemia, diabetic macular oedema
DIABETIC RETINOPATHY, PROLIFERATIVE DIABETIC RETINOPATHY, DIABETIC MACULAR OEDEMA, RETINA, HYPERPROLACTINEMIA
Elevation of systemic prolactin leads to the intraocular accumulation of vasoinhibin, a proteolytic fragment of prolactin that inhibits the excessive permeability and growth of blood vessels in the retina.The prokinetic oral medication, levosulpiride, induces hyperprolactinemia and elevates the levels of vasoinhibin i...
PMC10858020
Acknowledgements
The authors acknowledge the substantial contribution of Nancy Sánchez Martínez and Graciela Ibarra Vargas for the assessment and interpretation of optometry, optical coherence tomography, and fluorescein angiography data; Fernando López Barrera for statistical analysis, and Jessica Gonzalez Norris for editing the manus...
PMC10858020
Author contributions
TB
CDN-A, MLR-O, RG-F, PR-N, EL-S, TB, GME, JT, and CC conceived and designed the study; CDN-A, ML, EA-C, RG-F, MG-R, YV-G, PR-N, NP, and JFR-M acquired data; CDN-A, ML, EA-C, MLR-O, RG-F, MG-R, YV-G, PR-N, JFR-M, JS, GR-H, LS-M, ND-L, TB, GME, JT, and CC analysed and interpreted the data; CC wrote the manuscript and obta...
PMC10858020
Funding
This work was supported by the Consejo Nacional de Humanidades, Ciencias y Tecnologías (CONAHCYT) (grants 247164, 289568, and A1-S-9620B) and Universidad Nacional Autónoma de México (UNAM) (grant 405PC) to CC. The funding organisations had no role in the design or conduct of this research.
PMC10858020
Data availability
All original data generated or analysed during this study are included in this published article.
PMC10858020
Competing interests
TB
The authors declare the following broadly competing interest: CC, GME, JT, and TB are inventors of a submitted patent application (WO/2021/098996). The Universidad Nacional Autónoma de México (UNAM) and the authors JT and TB are owners of the pending patent.
PMC10858020
References
PMC10858020
Keywords
pain, Osteoarthritis, OA, OA symptoms
DISEASE, DISEASE PROGRESSION, DEGENERATIVE, OSTEOARTHRITIS
Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and patient-specific manner. This complexity has contributed to refractory responses to various treatments. MSCs have shown promise as multimodal therapeutics in mit...
PMC10229578
Subject terms
PMC10229578
Introduction
PMC10229578
Overview of osteoarthritis
TNF-α, Osteoarthritis, OA, tumor necrosis, arthritis
OSTEOARTHRITIS, TUMOR NECROSIS, DISEASE, ARTHRITIS, INFLAMMATION, PATHOGENESIS
Osteoarthritis (OA) is the most common form of arthritis, affecting an estimated 650 million people (654.1 [95% CI, 565.6–745.6]) aged 40 and older worldwide as of 2020, with an incidence of 203 per 10,000 person-years [95% CI, 206–331] [OA imposes socioeconomic burdens due to its morbidity, which results in reduced da...
PMC10229578
Mesenchymal stromal cells (MSCs) for the treatment of OA
OA, OA [
MSCs are attractive therapeutic candidates for OA due to their multimodal mechanisms of action, including their immunomodulatory properties. MSCs modulate the inflammatory cytokine milieu and immune cell responses in the joint via the release of secreted paracrine factors and extracellular vesicles (EVs) and through ho...
PMC10229578
Culture-expanded MSCs and randomized, controlled OA clinical trial results
PMC10229578
RCT patient populations
pain
DISEASE
To further understand the differential responses to MSC treatments, we further investigated the heterogeneous OA patient populations enrolled in these trials. Some trials, including those of Freitag et al. [Fourteen out of fifteen RCTs reviewed in this section classified patients by KL grade, typically enrolling patien...
PMC10229578
MSC dose comparisons in RCTs
The studies included in RCT analyses used a range of doses from 3.9 × 10Differential median baseline WOMAC total scores for the 10 × 10Lamo-Espinosa et al. conducted a subsequent 4-year follow-up study with 27 of the 30 patients [Similarly, Chen and Hu et al. demonstrated improvements in overall WOMAC scores at 48 week...
PMC10229578
Repeat MSC injection RCTs
There are only three published RCTs in which repeat MSC intra-articular injections were administered. Freitag et al. used cryopreserved autologous MSC(AT) at doses of 100 × 10Interestingly, Freitag’s group initially included a fourth arm of 40 × 10Conversely, the design of the Matas et al. trial included a control grou...
PMC10229578
Autologous vs. allogeneic MSCs in RCTs
RCTs investigating autologous MSCs made up the majority (9/15) of the studies reviewed, while the remaining (6/15) studies investigated MSCs of allogeneic origin. The autologous tissue of origin was split between bone marrow (5/9) and adipose tissue (4/9), while allogeneic sources were split between adipose tissue (2/6...
PMC10229578
MSC mechanisms of action in knee OA
DISEASE, ACUTE GVHD
Despite the completion of 15 peer-reviewed RCTs, there is limited evidence on the clinical mechanism of action of MSCs in OA. An improved understanding of the mechanism of action would be beneficial in the following ways: (i) it would facilitate the design of improved MSC therapies with properties tailored to achieve t...
PMC10229578
MSC anti-inflammatory and immunomodulatory effects on OA
inflammation, OA
INFLAMMATION, DISEASE, KNEE OSTEOARTHRITIS, PATHOPHYSIOLOGY, SECONDARY
MSC-mediated anti-inflammatory and immunomodulatory effects on OA inflammation are also known to play a central role in OA, with both innate and adaptive mediators involved in the pathophysiology [Evidence of the anti-inflammatory and immunomodulatory functionality of MSCs has been extensively reviewed in various precl...
PMC10229578
Clinical evidence of MSC immunomodulation in OA
While the findings of preclinical studies (extensively reviewed [Systemic and local levels of inflammatory biomarkers after intra-articular MSC injections have also been investigated in recent knee OA trials. A study by Li et al. demonstrated systemic anti-inflammatory effects of MSC(M) injections and platelet lysate (...
PMC10229578
Other potential mechanisms
synovitis, bone marrow lesions, fibrosis
CRITICAL LIMB ISCHEMIA, SYNOVITIS, DISEASE, FIBROSIS, PATHOPHYSIOLOGY, IDIOPATHIC PULMONARY FIBROSIS, OSTEOPHYTE
In addition to having immunomodulatory and chondroprotective effects in OA, MSCs may act through a variety of other mechanisms that target multiple tissues within the joint. These mechanisms include antifibrotic and angiogenic effects, which are interrelated with immunomodulation. In particular, the pro-angiogenic mech...
PMC10229578
Influence of MSC immunomodulatory basal fitness on their mechanisms of action
alloantibody
PROLIFERATION, RECRUITMENT
Several factors can influence the fitness and overall phenotype of MSCs that may in turn influence their mechanisms of action, as discussed here with emphasis on effects mediating immunomodulatory fitness. Donor heterogeneity represents a major variable and includes a multitude of factors, such as donor health status, ...
PMC10229578
Summary of current knowledge on MSC mechanisms of action in OA
There is limited clinical evidence on MSC mechanisms of action in OA. Recent clinical data have supported immunomodulation as a relevant mechanism of action for MSCs in OA [
PMC10229578
Roadmap for successful MSC OA trials
PMC10229578
Selecting the right OA patient endotype for MSC therapies
OA, inflammation, synovial inflammation, pain, heterogeneous disease
INFLAMMATION
OA is a heterogeneous disease, and at least six clinical phenotype subsets have been identified [Categorizing OA patients with the inflammatory phenotype (based on synovial inflammation) may be most relevant to MSC therapies with their proposed anti-inflammatory mechanisms of action. Indeed, the current most effective ...
PMC10229578
Designing the right MSC therapeutic product for OA
alloreactions
HYPOXIC, DISEASE
As discussed above, the immunomodulatory basal fitness of MSCs, which can be modulated by age, sex, BMI, comorbidities, manufacturing parameters and cryopreservation and can be quantified by a range of quantitative CQAs [Functional high-content in vitro potency assays that are relevant to the mechanisms of action may a...
PMC10229578
Considerations for successful clinical trial design for MSC products for OA
osteoarthritis, OA
OSTEOARTHRITIS, EMA
Clinical trials investigating MSC treatments in OA should incorporate additional readouts on putative mechanisms of action to facilitate future regulatory approvals of MSC products in OA and to tailor next-generation MSC therapies that have specific therapeutic properties and CQAs that are tuned for relevance in OA (Fi...
PMC10229578
Summary
P., OA, pain
DISEASE PROGRESSION, DISEASE
Even with 15 completed RCTs, the sample size of 610 treated patients (with MSCs and control treatments) is relatively small to reach definitive conclusions on optimal dosing, baseline patient endotype and phenotype, delivery strategies, MSC sourcing, manufacturing, and overall treatment efficacy. Nonetheless, the findi...
PMC10229578
Acknowledgements
Arthritis
ARTHRITIS
This research was funded by the Canadian Institutes of Health Research (CIHR) (PJT-166089) and the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2018-05737). This work is in part supported by the Schroeder Arthritis Institute via the Toronto General and Western Hospital Foundation (Universi...
PMC10229578
Competing interests
SV has 60% ownership of Regulatory Cell Therapy Consultants Inc., which does not conflict with this paper in any way. KR and GC declare no conflicts of interest.
PMC10229578
References
PMC10229578
1. Introduction
cancer [Behaviors, Dietary behaviors, food-seeking behaviors, pancreatic and gastrointestinal hormones, satiety, dietary behaviors
SECONDARY, TYPE 2 DIABETES MELLITUS, CHRONIC DISEASES, HEART DISEASE
Hunger and satiety are controlled by several physiological mechanisms, including pancreatic and gastrointestinal hormones. While the influence of exercise and fasting have been described individually, in relation to these hormones, there is a paucity of work showing the effects of the two modalities (fasting and exerci...
PMC10142171
2. Materials and Methods
The study was designed to compare the impact of fasting with and without an initiating bout of exercise on appetite hormones (PYY, PP, GLP-1, GIP, insulin, ghrelin, and leptin). To accomplish this purpose, we used a randomized crossover design with conditions counterbalanced. All participants were exposed to two treatm...
PMC10142171
2.1. Participants
word of mouth
A total of 11 men and 9 women were recruited to participate in the study. Participants were recruited using advertisements, fliers, and word of mouth. Baseline physical activity was self-reported. Based on this self-report, 5% of participants participated in less than 30 min of exercise per week, 10% participated in 30...
PMC10142171
2.2. Measurements
PMC10142171
2.2.1. Anthropometric Measurements
Body mass and height were assessed at the beginning of each condition. Participants were assessed with their shoes removed and wearing a t-shirt and athletic shorts. Body mass was assessed using a digital scale accurate to ±0.1 kg (Seca, Hamburg, Germany). Height was assessed using a stadiometer (Seca, Hamburg, Germany...
PMC10142171
2.2.2. Plasma Hormone Levels
BLOOD, EMD
Blood draws were taken every 12 h of each fast (0, 12, 24, and 36 h). Samples were centrifuged for 15 min within 10 min of collection and then stored at −80 °F. Ghrelin, GLP-1, PYY, PP, leptin, insulin, and GIP were quantified using a standard 96-well multiplex human metabolic hormone magnetic bead panel according to t...
PMC10142171
2.3. Procedures
PMC10142171
2.3.1. Screening
FOOD ALLERGIES
Potential participants were emailed a link to an online survey, which was used to ensure all inclusion criteria for the study were met. In the survey, participants were asked to complete the PAR-Q, a food preference questionnaire, and report any food allergies. Candidates who qualified were invited to participate in th...
PMC10142171
2.3.2. Orientation
Dietary and sleep
Participants gave informed consent prior to participation in the study. Each participant was familiarized with the study procedures and informed of the purpose of the study. During the testing period, participants were asked to go about their normal daily activities while avoiding strenuous activity, including cardiova...
PMC10142171
2.3.3. Standardized Meals
To initiate each fast, a standardized meal was given to each participant. Equations validated for reliability and accuracy by Hall et al. [
PMC10142171
2.3.4. Treatment Sessions
Participants were asked to maintain normal eating habits leading up to each fast and to abstain from eating for at least four hours before consuming the standardized meal at the initiation of their fast in an effort to normalize blood markers and prevent pre-fast caloric loading [
PMC10142171
2.3.5. Exercise Protocol
Exercise protocols were completed on a treadmill at a speed and grade designed to bring the estimated heart rate reserve (HRR) of each participant to 70%. This type of exercise is considered intense [The following formula was used to estimate maximal HR [A strap-on heart rate monitor (Garmin, Olathe, KS, USA) was fitte...
PMC10142171
2.4. Statistical Analysis
Means and standard deviations were used to describe participant data. The primary factors in the statistical models were condition and sex. The two levels of the condition variable were fasting alone and fasting with exercise. The sample size was calculated a priori. Using an alpha of 0.05, a beta of 0.20, and an effec...
PMC10142171
4. Discussion
nutritional ketosis, depressed, appetite
INSULIN SENSITIVITY
Recent research indicates that fasting may lead to weight loss but may also increase concentrations of ghrelin while reducing concentrations of GLP-1, PYY, and PP throughout the fast [We found that completing a bout of vigorous exercise at the beginning of a fast depressed concentrations of ghrelin by 17% while raising...
PMC10142171
Limitations and Strengths
This was an acute study evaluating the change in appetite hormones over the course of a single 36-h fast. While the results are informative, we are unable to describe how these results may change with repeated fasts over time. In addition, while each participant abstained from food for four hours prior to presenting at...
PMC10142171
5. Conclusions
This study found that initiating a fast with a bout of vigorous treadmill exercise lowers ghrelin and elevates GLP-1 concentrations compared to fasting alone. However, the relationship between hormone concentration and hunger seems to be complicated and the changes that we observed in GLP-1 and ghrelin did not seem to ...
PMC10142171
Author Contributions
L.E.D.
Conceptualization, L.S.D., B.T.B., L.E.D., L.A.T. and B.W.B.; methodology, L.S.D., B.T.B., L.E.D., L.A.T. and B.W.B.; software, L.S.D.; validation, L.S.D., B.T.B., L.E.D., L.A.T. and B.W.B.; formal analysis, B.T.B., L.E.D., L.A.T. and B.W.B.; investigation, L.S.D., C.J.C., G.R.L. and J.L.C.; data curation, L.S.D. and B...
PMC10142171
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Brigham Young University (IRB2019-319, approved 14 October 2019).
PMC10142171
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
PMC10142171
Data Availability Statement
The data supporting the reported results are available on the Open Science Framework at
PMC10142171
Conflicts of Interest
The authors declare no conflict of interest.
PMC10142171
References
Participant flow diagram.Concentrations of ghrelin (Demographic characteristics of participants.Hormone concentrations (pg/mL) at four time points during a 36 h fast with or without exercise.Mean ± standard deviation. F and Differences in area under the curve for fasting with and without exercise over 36 h.
PMC10142171
Objective
weight gain
PRETERM BIRTH, COMPLICATIONS
Preterm birth is one of the most important health problems in the world. Feeding intolerance is one of the most common and serious complications of premature infant. The purpose of this study was to explore the effect of Chinese pediatric Tuina on the prevention of feeding intolerance in favour of weight gain in premat...
PMC10782327
Methods
weight gain
PREMATURE
A prospective randomized controlled study was conducted in the Department of Neonatology in our hospital. Premature infants were recruited and randomly assigned to an intervention group or a control group. Premature infants in the intervention group received a Chinese pediatric Tuina intervention by professional chirop...
PMC10782327
Result
gastrointestinal bleeding, liver insufficiency
GASTROINTESTINAL BLEEDING, NECROTIZING ENTEROCOLITIS
After 1 week of intervention, the body weight (2.5±0.5 vs 2.0±0.4, p=0.038), head circumference (32.8±1.7 vs 29.9±1.4, p=0.041), albumin (34.6±5.8 vs 28.4±6.1, p-0.026) and prealbumin (155.8±35.2 vs 113.6±36.8, p=0.021) of preterm infants in the intervention group were significantly better than those in the control gro...
PMC10782327
Conclusion
weight gain
Chinese pediatric Tuina can effectively prevent the occurrence of feeding intolerance in premature infants and be conducive to the weight gain and improving nutritional status of premature infants.
PMC10782327
Introduction
PRETERM BIRTH, COMPLICATIONS
Preterm birth is one of the most important health problems in the world.Due to their low gestational age and low weight at birth, the immature development of various systems and organs, poor sucking and swallowing function, and insufficient secretion of digestive enzymes, preterm infants are prone to various complicati...
PMC10782327