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Conclusion: | DISORDER | Delivering MS-BPD in conjunction with an online psychoeducational intervention was not found to provide additional benefit over and above access to an online intervention alone. In accordance with national guidelines, carer interventions should be routinely offered by youth mental health services as part of early intervention programmes for borderline personality disorder. Further research is warranted into which interventions work for whom, carers’ preferences for support and barriers to care. | PMC10619189 |
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Background | overload and distress, guilt, MS-BPD, Borderline personality disorder, personality disorders, adversity, pain, mental disorder, BPD | Borderline personality disorder (BPD) is a severe mental disorder that usually has its onset during adolescence and early adulthood (The families and friends (henceforth ‘carers’) of people with BPD features also report adversity in terms of elevated burden (or negative appraisal of the experiences of caregiving), distress, grief, disempowerment and mental ill health (Recent systematic reviews have concluded that there is preliminary support for the effectiveness of interventions for carers of individuals with personality disorders, with evidence for reducing burden, emotional burnout, pain, grief, guilt, overload and distress, and for improving relationship skills and family climate (To the authors’ knowledge, only three published interventions have been designed specifically for the carers of young people and implemented within an early intervention framework: Making Sense of BPD (MS-BPD) (While these findings are promising, a rigorous evaluation of carer interventions using an RCT design with an active comparison group is warranted. Evaluations to date have relied on carers self-referring in response to public advertising (e.g. This study aimed to evaluate the effectiveness of the in-person MS-BPD group, delivered in conjunction with an Online BPD psychoeducation programme (MS-BPD + Online), compared with the Online programme alone, in improving carer outcomes. It was hypothesised that MS-BPD + Online would be associated with superior results at the 7-week endpoint. | PMC10619189 |
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Methods | PMC10619189 |
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Study design | BPD | The study was a single-centre, parallel group, single-blinded, clustered, partially-nested RCT. Randomisation was by ‘unit’, that is, by the individual carer or group of carers per young person with BPD features. It was approved by the Melbourne Health Human Research Ethics Committee (HREC2014.105) and prospectively registered (ACTRN12616000304437). The trial protocol has been published ( | PMC10619189 |
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Study setting | The study was conducted at Orygen’s Helping Young People Early (HYPE) programme ( | PMC10619189 |
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Key inclusion and exclusion criteria | BPD | The young people with BPD features (‘clients’) were aged 15–25 years (inclusive) and the carers were their relatives, partners or friends. A carer’s participation was not dependent on their young person also consenting to participate. | PMC10619189 |
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Discontinuation and withdrawal | EVENT | Carers were discontinued or withdrawn if their participation interfered with appropriate clinical management of the client’s risk to self or others, consent was revoked, or an event (e.g. disruptive behaviour in the group setting) led to discontinuation from the intervention at the discretion of the investigators. | PMC10619189 |
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Treatment conditions | BPD, early-stage BPD, mental illness | SESSION | The two treatment arms were Online and MS-BPD + Online and the treatment period was 15 days. Rather than utilise TAU or a waiting list as comparators, which may not be operationalised consistently or have the same effect within and between trials, this trial aimed for a more rigorous design by comparing two manualised, standardised, active interventions (Online comprised two self-directed modules of written material and video interviews with experienced clinicians, clients and parents (available at MS-BPD + Online comprised the Online modules and MS-BPD, a manualised group programme developed for the carers of young people with early-stage BPD. Informed by the principles of CAT and the HYPE model of care, MS-BPD comprises three 2-hour in-person group sessions, run during the evening over three consecutive weeks. Session 1 (‘What is BPD?’) psychoeducation content includes an explanatory model of BPD; normal development; causes of BPD; the developmental context of BPD in young people; and the rationale for thinking about relationships in the treatment of BPD. Session 2 (‘BPD Treatment’) content includes an introduction to early intervention for BPD and common interpersonal difficulties and possible ways to resolve these. Session 3 (‘Looking After Yourself’) content includes managing risk from a relational perspective; supporting carer self-efficacy and well-being; and additional resources. Groups were facilitated by clinicians and (for Session 3) a lived experience expert, who has cared for a young person with mental illness. Treatment integrity was maintained via facilitator supervision, use of the manual and standardised programme resources (e.g. presentation slides). MS-BPD + Online treatment completion was defined as attending two or more MS-BPD sessions. | PMC10619189 |
Measures | The primary outcome was the combined negative appraisal subscales (sometimes referred to as ‘negative experience of caregiving’ or ‘burden’) of the Experience of Caregiving Inventory (ECI) ( | PMC10619189 |
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Procedure | BPD | Consecutive referrals to HYPE were considered for an invitation to participate in the RCT. Written informed consent was obtained from all participants (and from a parent/legal guardian for individuals under 18 years of age). Upon completion of baseline questionnaires, carers were randomly and consecutively assigned as a ‘unit’ (defined by their relationship to the young person with BPD features) in a 1:1 ratio, using randomised permuted blocking, and stratified by client’s sex and age (<18 years cut-point). The interventions were delivered in seven rounds, approximately 12 weeks apart, between March 2016 and September 2017. Follow-up questionnaires were issued to all carers at week 7, i.e., 4 weeks post-intervention (including those who had discontinued the intervention), and carers had up to 4 weeks to complete these. Data regarding the young person were extracted from their medical records. | PMC10619189 |
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Statistical analysis | BLIND | An intent-to-treat (ITT) analysis with all carers who provided follow-up data was conducted by a statistician who was blind to group allocation, followed by a per-protocol (PP) analysis with carers who completed treatment. A hierarchical linear modelling approach was used in order to account for the nested structure of the data (The power analysis was based on assumptions that the average unit comprised 1.5 carers, the intraclass correlation coefficient within units was 0.2, the correlation within rounds was 0.03 and that each round would comprise 9.4 carers. Using these parameters, the maximum design effect was 1.24. Assuming a 0.5 correlation between baseline and outcome measures, a total sample of 54 units was deemed to have 80% power to detect a difference of 0.5 standard deviations (medium size difference) between the arms. | PMC10619189 |
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Results | PMC10619189 |
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Participant flow | DISORDER | Two hundred and eighty-one carers were considered for inclusion in the study and 103 were excluded. The most common reasons for exclusion were that consent was not completed before the client was discharged from HYPE (The 73 carers were family or friends of 53 clients. Data were not collected on seven clients because consent could not be obtained from them prior to discharge from HYPE (CONSORT diagram.Bold represents carers and () represents units. MS-BPD, Making Sense of Borderline Personality Disorder group program. | PMC10619189 |
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Treatment engagement | SD | Of the carers in the ITT analysis randomised to MS-BPD + Online, 20 (57.1%) completed treatment, while 12 (34.3%) did not attend any MS-BPD sessions. The carers spent a mean of 48.9 minutes (SD = 146.9) logged into the online intervention, visiting a mean of 0.7 (SD = 1.7) times. Carers were not logged out after periods of inactivity. Six (17.1%) carers used the online intervention for more than 45.2 minutes and 25 (71.4%) did not log in at all. The carers had a mean of 0.9 (SD = 1.9) and 0.4 (SD = 1.1) phone contacts and 1.4 (SD = 1.9) and 0.5 (SD = 1.0) face-to-face contacts with the HYPE family work clinician and family peer support worker, respectively.Of the carers in the ITT analysis randomised to Online, 17 (44.7%) completed treatment and 14 (36.8%) did not log in. Carers spent a mean total of 420.3 minutes (SD = 1594.6) logged into the online intervention, visiting a mean of 2.9 (SD = 3.8) times. They had a mean of 0.9 (SD = 1.9) and 0.3 (SD = 0.7) phone contacts and 0.6 (SD = 1.3) and 0.1 (SD = 0.4) face-to-face contacts with the HYPE family work clinician and family peer support worker, respectively. | PMC10619189 |
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ITT analysis | SE, BPD, Life–8, borderline personality disorder | DISORDER, SECONDARY | Absolute repeated-measures effect sizes for pre-post differences by group ranged from very small (Cohen’s Pre-post differences on outcome variables by group.MS-BPD: Making Sense of BPD; BPD: borderline personality disorder; ECI: Experience of Caregiving Inventory; CISS: Coping Inventory for Stressful Situations; PDKASQ: Personality Disorder Knowledge Attitudes and Skills Questionnaire; K-10: Kessler Psychological Distress Scale; FQ: Family Questionnaire; AQoL-8D: Assessment of Quality of Life–8 Dimensions; Q-LES-Q-SF: Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form.There were no significant differences detected between the MS-BPD + Online and Online groups for the primary and secondary outcomes (Estimated impact of MS-BPD + Online on outcome measures.MS-BPD: Making Sense of BPD; BPD: borderline personality disorder; M: unadjusted mean; SD: standard deviation; CI: confidence interval; SE: standard error; AQoL-8D: Assessment of Quality of Life–8 Dimensions; Q-LES-Q-SF: Quality of Life Enjoyment and Satisfaction–Short Form. | PMC10619189 |
PP analysis | SECONDARY | No significant differences between the MS-BPD + Online and Online groups were detected for the primary and secondary outcome measures, when only treatment completers were analysed (all | PMC10619189 |
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References | PMC10619189 |
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1. Introduction | toxicity, dyslipidemia | HYPERTENSION, DYSLIPIDEMIA | This study evaluated the efficacy and safety of 20 mg of Cuban policosanol in blood pressure (BP) and lipid/lipoprotein parameters of healthy Japanese subjects via a placebo-controlled, randomized, and double-blinded human trial. After 12 weeks of consumption, the policosanol group showed significantly lower BP, glycated hemoglobin (HbAPolicosanol is a mixture of aliphatic alcohols ranging from 24–34 carbon atoms [Many studies examining the molecular mechanisms for the efficacy of Cuban policosanol reported that the encapsulation of policosanol into HDL enhances the HDL functions and has anti-senescence and tissue regeneration effects by improving anti-glycation, anti-apoptosis, and cholesteryl transfer protein (CETP) inhibition [Although many studies reported the efficacy of policosanol in humans, particularly in a Korean population, there has been no study on the effects of Cuban policosanol on the lipid parameters of a Japanese population. The Japanese population shows the unique features of a higher HDL-C level than western populations, with a higher portion of those with a genetic deficiency of CETP [The current study examined the effect of policosanol consumption on the blood lipid parameters of a Japanese population; healthy Japanese subjects who had a normal blood pressure (BP) and normolipidemic (120 mg/dL < LDL < 160 mg/dL and >40 mg/dL of HDL) were recruited. The participants were randomized to consume 20 mg of policosanol or a placebo to compare the changes in BP, blood parameters, and lipid and lipoprotein parameters with a randomized and double-blinded test. After 12 weeks of consumption of policosanol or a placebo, blood was analyzed to assess the putative efficacy to improve the metabolic parameters of the heart, kidney, liver, or hidden toxicity. From the participants, HDL and LDL were purified individually, and the HDL functionality and LDL qualities, such as oxidized and glycated extent with antioxidant abilities, were analyzed.The antioxidant and anti-inflammatory properties of HDL were compared using zebrafish embryos by testing their developmental speed and survivability after injecting HDL in the presence of Zebrafish (The improvements of the quantity and quality of lipoproteins in blood are very important for evaluating the efficacy of policosanol or any nutraceutical to treat dyslipidemia and hypertension. In the current study, changes in the BP, lipid/lipoprotein parameters, and HDL functionalities were assessed after consuming Cuban policosanol for 12 weeks, using a randomized, double-blinded, placebo-controlled study. | PMC10048825 |
2. Results | PMC10048825 |
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2.1. Anthropometric and Blood Profiles | As shown in | PMC10048825 |
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2.2. Liver, Kidney, and Inflammatory Parameters | At week 12, the policosanol group showed 8.7% lower (At week 12, the placebo group had even higher γ-GTP and BUN levels than at week 0, even though no significance was detected. The placebo group showed a 16% higher BUN level than the policosanol group at week 12 (As listed in | PMC10048825 |
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2.3. Lipid and Lipoprotein Profiles | TG | After excluding the participants showing low compliance, who consumed a significantly more fat diet, heavy drinking, and smoking, during the 12-week consumption, the policosanol group (n = 15) showed 6.3% higher HDL-C (On the other hand, the TC and TG levels in the policosanol group were relatively unaffected at weeks 0, 4, 8, and 12. Repeated measures ANOVA of TC, TG, LDL-C, and RC levels during the 12 weeks showed no difference between the policosanol group (n = 15) and the placebo group (n = 17) in terms of time and group interaction. On the other hand, at week 12, the policosanol group showed a 3% lower TG/HDL-C ratio than the placebo group ( | PMC10048825 |
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2.4. VLDL Particle Observation and Composition Analysis | As shown in As shown in As shown in As shown in | PMC10048825 |
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2.5. LDL Particle Observation and Composition Analysis | TEM | TEM showed a 5% increase in LDL particle size (531 ± 8 nmAs shown in | PMC10048825 |
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2.6. Electromobility of LDL and Oxidation Extent | A comparison of the LDL electromobility under the nondenatured state ( | PMC10048825 |
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2.7. Change in apoA-I Contents in HDL | SDS-PAGE analysis of HDL | PMC10048825 |
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2.8. Paraoxonase Activities in HDL | As shown in | PMC10048825 |
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2.9. Ferric Ion Reduction Ability of HDL | At the same protein concentration (2 mg/mL), there was no difference in the ferric ion reduction ability (FRA) for HDL | PMC10048825 |
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2.10. Embryo Survivability | As shown in As shown in | PMC10048825 |
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3. Discussion | neurotoxicity, CML | CML | Cuban policosanol supplementation in Korean participants increased the serum HDL-C level and enhanced the HDL functionality to inhibit the oxidation and glycation of LDL and HDL [Many studies were carried out with different policosanol doses in different countries and ethnic populations, such as Caucasian [On the other hand, with the exception of Cuban policosanol [After 12 weeks of Cuban policosanol consumption, the systolic and diastolic BP were reduced significantly but still in the normal range of up to 7% (The hepatic functions were also improved remarkably by the policosanol consumption with lower serum AST, ALT, γ-GTP, and BUN levels (Adding CML to HDL for 48 h increased the production of yellowish glycated fluorescence with proteolytic degradation of apoA-I and the loss of paraoxonase activity [The CML also exhibited neurotoxicity and embryotoxicity in adult zebrafish and its embryo [Regarding the mechanism of action, policosanol consumption resulted in an increase in HDL-C and apoA-I content in HDL via CETP inhibition, as reported elsewhere [As summarized in A limitation of this study was that the data on lifestyle, such as diet consumption, smoking, and alcohol drinking frequency, exercise intensity, and time were obtained from self-reported questionnaires. The validation of these data for diet, smoking, drinking, and exercise might be intricate for distinguishing the consumption of policosanol or placebo effect. In addition, methodological and practical difficulties due to space limitation in rotor for ultracentrifugation were related with the selection of participants. To achieve more reliable and accurate results, the four steps of ultracentrifugation for a total of 96 h and subsequent dialysis for each 24 h, from VLDL, LDL, HDLIn conclusion, 12 weeks of Cuban policosanol (Raydel | PMC10048825 |
4. Materials and Methods | PMC10048825 |
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4.1. Policosanol | Raydel | PMC10048825 |
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4.2. Participants | allergies, diabetes | METABOLIC DISORDER, MAY, DYSLIPIDEMIA, ALLERGIES, HYPERTENSION, DIABETES | Healthy male and female volunteers with normal lipid levels and normal blood pressure were recruited nationwide in Japan via newspaper and internet advertisements between September 2021 and May 2022. The inclusion criteria were LDL-C levels in the normal range (120–160 mg/dL) and age between 20 and 65 years old. The exclusion criteria were as follows: (1) Maintenance treatment for metabolic disorder, including dyslipidemia, hypertension, and diabetes; (2) severe hepatic, renal, cardiac, respiratory, endocrinological, and metabolic disorder disease; (3) allergies; (4) heavy drinkers, more than 30 g of alcohol per day; (5) taking medicine or functional food products that may affect the lipid metabolism, including raising HDL-C or lowering LDL-C concentration, and lowering triglyceride concentration; (6) current and past smoker; (7) women in pregnancy, lactation, or planning to become pregnant during the study period; (8) person who had more than 200 mL of blood donation within 1 month or 400 mL of blood within 3 months before starting this clinical trial; (9) a person who participated in other clinical trials within the last 3 months or currently is participating in another clinical trial; (10) those who consumed more 2000 kcal per day; (11) others considered unsuitable for the study at the discretion of the principal investigator. The study was approved by the Koseikai Fukuda Internal Medicine Clinic (Osaka, Japan, IRB approval number 15000074, approval date on 18 September 2021). | PMC10048825 |
4.3. Study Design | 120 mg/dL ≤ LDL | This study was a double-blinded, randomized, and placebo-controlled trial with a 12-week treatment period. After an initial screening, 72 subjects (Male 36, Female 36) with 120 mg/dL ≤ LDL <160 mg/dL were selected as shown in After allocating the participants into two groups, they were directed to take two tablets per day containing policosanol 10 mg (RaydelAll participants received advice to avoid excess food (<1800 and 1500 kcal for men and women, respectively, per day), cholesterol (<600 mg per day), and alcohol drinking (<30 and <15 g of ethanol for men and women, respectively, per day), and no smoking both direct and indirect, which can interfere with the lipoprotein metabolism. They were also instructed to avoid intense exercise (<30 min daily at 60–80% maximum capacity). After 12 weeks of consumption, the blood parameters of all participants who completed the program were analyzed. Then, the lipid and lipoprotein parameters were analyzed after excluding those who violated dietary and exercise guidelines, such as omitting daily consumption, overeating, a significantly more fat diet, smoking, and heavy drinking, and failed the other exclusion criteria after stratified analysis based on the self-reported questionnaire. | PMC10048825 |
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4.4. Anthropometric Analysis | KDS | The blood pressure was measured using an Omron HEM-907 (Kyoto, Japan) with a total of three times of measurements, and the average was recorded. The height, body weight, and body mass index (BMI) were measured individually using a DST-210N (Muratec KDS Co., Ltd., Kyoto, Japan). | PMC10048825 |
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4.5. Blood Analysis | After fasting overnight, blood samples were collected in ethylenediaminetetraacetic acid (EDTA)-coated tubes and centrifuged at 3000× | PMC10048825 |
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4.6. Isolation of Lipoproteins and Quantification | TG | Very low-density lipoproteins (VLDL, d < 1.019 g/mL), LDL (1.019 < d < 1.063), HDLFor each lipoprotein purified individually, the total cholesterol (TC) and TG levels were measured using commercially available kits (cholesterol, T-CHO, and TG, Cleantech TS-S; Wako Pure Chemical, Osaka, Japan). The protein concentrations of the lipoproteins were determined using a Lowry protein assay, as modified by Markwell et al. [ | PMC10048825 |
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4.7. Quantification of Oxidation Extent in VLDL and LDL | The degree of oxidation of the individual VLDL (0.5 mg/mL of protein) and LDL (1.0 mg/mL of protein) was assessed by measuring the concentration of oxidized species in the lipoproteins using the thiobarbituric acid reactive substances (TBARS) method with malondialdehyde (MDA) as a standard [ | PMC10048825 |
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4.8. Oxidation of VLDL and LDL | Oxidized VLDL (oxVLDL) and LDL (oxLDL) were produced by incubating the native VLDL (0.5 mg/mL of protein) or LDL fraction (1.0 mg/mL of protein), which was purified from young and healthy males, with CuSO | PMC10048825 |
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4.9. Agarose Electrophoresis | The relative electromobility of the VLDL and LDL (5 μg of protein) was compared under a non-natured state on 0.5% agarose gel (120 mm length × 60 mm width × 5 mm thickness). The electrophoresis was carried out with 50 V for 1 h in Tris-acetate-EDTA buffer (pH 8.0), as described previously [ | PMC10048825 |
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4.10. Electron Microscopy | TRANSMISSION, TEM | Transmission electron microscopy (TEM, Hitachi H-7800; Ibaraki, Japan) at the Raydel Research Institute (Daegu, Korea) was performed at an acceleration voltage of 80 kV. VLDL and LDL were stained negatively with 1% sodium phosphotungstate (PTA; pH 7.4) with a final apolipoprotein concentration of 0.3 mg/mL in TBS. Five μL of the lipoprotein suspension was blotted with filter paper and replaced immediately with a 5 μL droplet of 1% PTA. After a few seconds, the stained lipoprotein fraction was blotted onto a Formvar carbon-coated 300 mesh copper grid and air-dried. The shape and size of the LDL were determined by TEM at 40,000× magnification, according to a previous report [ | PMC10048825 |
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4.11. Paraoxonase Assay | The paraoxonase-1 (PON-1) activity in HDL | PMC10048825 |
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4.12. Ferric Ion Reduction Ability Assay | The ferric ion reduction ability (FRA) was determined using the method reported by Benzie and Strain [ | PMC10048825 |
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4.13. Electrophoretic Patterns of HDL | The relative compositions of the apolipoproteins and band intensity of apoA-I in HDL | PMC10048825 |
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Author Contributions | Conceptualization, K.-H.C.; methodology, S.-H.B., D.-J.K., H.-S.N. and H.N.; writing—original draft preparation, K.-H.C.; supervision, K.-H.C.; data curation and investigation, T.K. and Y.U. All authors have read and agreed to the published version of the manuscript. | PMC10048825 |
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Institutional Review Board Statement | The protocol of human blood donation was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Koseikai Fukuda Internal Medicine Clinic (Osaka, Japan), with the IRB approval number 15000074, approval date on 18 September 2021. The animal study protocol was approved by the Committee of Animal Care and Use of Raydel Research Institute (approval code RRI-20-003). | PMC10048825 |
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Informed Consent Statement | Not applicable. | PMC10048825 |
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Data Availability Statement | The data used to support the findings of this study are available from the corresponding author upon reasonable request. | PMC10048825 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10048825 |
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References | high-density lipoproteins-cholesterol, low-density lipoproteins, dyslipidemia | CML, TEM, DYSLIPIDEMIA | TEM image of VLDL (Comparison of the electromobility (TEM image of LDL (Comparison of the electromobility (Changes in the apoA-I contents in HDL, HDL-C, and %HDL-C in TC during 12 weeks of consumption of policosanol and placebo. HDL-C, high-density lipoproteins-cholesterol; TC, total cholesterol. (Comparison of the paraoxonase (PON-1) activity in HDLComparison of the ferric ion reduction ability (FRA) of HDLComparison of the protective activity of HDLProposed mechanism of policosanol to improve blood pressure and dyslipidemia after 12 weeks of consumption. apoA-I, apolipoprotein A-I; AST, aspartate transferase; ALT, alanine aminotransferase; CML, carboxymethyllysine; FRA, ferric ion reduction ability; γ-GTP, gamma-glutamyl transpeptidase; HbA1c, hemoglobin A1c; LDL, low-density lipoproteins; MDA, malondialdehyde; PON-1, paraoxonase-1; TC, total cholesterol; TG, triglyceride; VLDL, very low-density lipoproteins.Study design and participant allocation for analysis. Anthropometric profiles and blood parameters between the policosanol (20 mg) and placebo groups *.*, Data are expressed as the mean ± SEM (standard error of the mean). Repeated measures ANOVA of blood lipid parameters between the policosanol (PCO, 20 mg) and placebo groups *.*, Data are expressed as the mean ± SEM (standard error of the mean). Estimated statistical power is 92% based on the calculation using the program G*Power 3.1.9.7 (G*Power from University of Düsseldorf, Düsseldorf, Germany). Lipid compositions, oxidized extent, and extent of VLDL and LDL glycation between the policosanol and placebo groups.FI, fluorescence intensity (Ex = 370 nm, Em = 440 nm, 0.01 mg/mL of protein); MDA, malondialdehyde; TC, total cholesterol (μg/mg of protein); TG, triglyceride (μg/mg of protein); LDL, low-density lipoproteins; VLDL, very low-density lipoproteins. The data are expressed as the mean | PMC10048825 |
Background | Asymmetric walking gait impairs activities of daily living in neurological patient populations, increases their fall risk, and leads to comorbidities. Accessible, long-term rehabilitation methods are needed to help neurological patients restore symmetrical walking patterns. This study aimed to determine if a passive unilateral hip exosuit can modify an induced asymmetric walking gait pattern. We hypothesized that a passive hip exosuit would diminish initial- and post-split-belt treadmill walking after-effects in healthy young adults. | PMC10339586 |
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Methods | We divided 15 healthy young adults evenly between three experimental groups that each completed a baseline trial, an adaptation period with different interventions for each group, and a post-adaptation trial. To isolate the contribution of the exosuit we compared a group adapting to the exosuit and split-belt treadmill (Exo-Sb) to groups adapting to exosuit-only (Exo-only) and split-belt only (Sb-only) conditions. The independent variables step length, stance time, and swing time symmetry were analyzed across five timepoints (baseline, early- and late adaptation, and early- and late post-adaptation) using a 3 × 5 mixed ANOVA. | PMC10339586 |
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Results | We found significant interaction and time effects on step length, stance time and swing time symmetry. Sb-only produced increased step length asymmetry at early adaptation compared to baseline (p < 0.0001) and an after-effect with increased asymmetry at early post-adaptation compared to baseline (p < 0.0001). Exo-only increased step length asymmetry (in the opposite direction as Sb-only) at early adaptation compared to baseline (p = 0.0392) but did not influence the participants sufficiently to result in a post-effect. Exo-Sb produced similar changes in step length asymmetry in the same direction as Sb-only (p = 0.0014). However, in contrast to Sb-only there was no significant after-effect between early post-adaptation and baseline (p = 0.0885). | PMC10339586 |
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Conclusion | The passive exosuit successfully diminished asymmetrical step length after-effects induced by the split-belt treadmill in Exo-Sb. These results support the passive exosuit’s ability to alter walking gait patterns. | PMC10339586 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12984-023-01212-w. | PMC10339586 |
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Keywords | PMC10339586 |
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Background | stroke | STROKE | Over 8 million people in the United States live with lingering symptoms following stroke [The utilization of novel perturbations to alter walking gait symmetry has produced short-term ambulation improvements. By utilizing these perturbations, the CNS can be trained to adapt to complex, unexplored environments through the integration of sensory feedback during ongoing movement [During walking each limb adapts independently to the environment, allowing for leg-specific responses to perturbations [Previously, researchers have used exoskeletons to manipulate spatiotemporal, kinematic, and kinetic movement characteristics. Robotic (active) exoskeletons use software and powered actuation systems to apply forces at specific times during a movement pattern, such as walking gait [Typically, wearable devices, such as exoskeletons, are used to provide assistance. However, they may also yield resistance to promote adaptations similar to those observed with split-belt perturbations. Recent studies have explored the use of exoskeletons [The specific objective of our study was to determine if a passive unilateral hip exosuit can diminish asymmetric walking gait patterns in healthy participants. In order to induce walking asymmetry in healthy participants, we used a split-belt treadmill. Previous studies found that the split-belt paradigm leads to asymmetrical walking patterns in healthy young adults when initially introduced and asymmetrical after-effects upon return to a tied configuration [ | PMC10339586 |
Methods | PMC10339586 |
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Participants | Fifteen healthy young adults (6 females, 9 males; 13 right-footed, 2 left-footed; age = 24.13 ± 2.47 years; mass = 72.2 ± 11.9 kg; height = 172.5 ± 9.8 cm; mean ± sd.) (Additional File | PMC10339586 |
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Experimental protocol | Data collection took place in the virtual reality lab in the Biomechanics Research building at the University of Nebraska. We allocated participants evenly into three parallel groups with five participants each: Exosuit-only (Exo-only), Split-belt only (Sb-only), and Simultaneous (Exo-Sb). All participants in each group walked on an instrumented Split-belt Treadmill (Bertec®, Columbus, Ohio) that sampled kinetic data at 1000 Hz. Each group completed a 3-minute baseline walking trial with the belts tied at 1.0 msWe measured kinematics at 100 Hz using a calibrated 16-camera motion capture system (Vicon Motion Systems, Ltd, Oxford, United Kingdom). Participants wore a close-fitting singlet and their preferred walking shoes throughout the entirety of the collection. We placed a marker set consisting of 33 retro-reflective markers (12.7 mm) on bony landmarks bilaterally on the feet (head of 1st and 5th metatarsal, base of the 2nd phalange, calcaneus, heel), shank (medial and lateral malleoli, tibial tuberosity, lateral shank), knee (medial and lateral epicondyles of the femur), thigh (lateral thigh, greater trochanter, ventral-distal thigh), and pelvis (anterior superior iliac spine, posterior superior iliac spine, sacrum) to track lower extremity kinematics following a modified Helen-Hayes marker set. We put the retro-reflective markers directly on the skin, on the surface of the singlet, or on top of the shoes over the foot landmarks. Participants wore a safety harness attached to a ceiling mount throughout all collection trials. The harness did not support body weight.
Protocol Set-up. Times, belt speeds, and trials for each experimental group. The time periods, Baseline (blue), Adaptation (red), and Post-adaptation (purple), are represented by the outlines. Numbers at the top represent the minutes spent in each section. D stands for dominant and ND stands for non-dominant. The color filling represents the individual belt velocities of the split-belt treadmill. Grey represents the standard velocity at 1.0 ms | PMC10339586 |
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Exosuit design | We assembled the passive unilateral exosuit based on previous designs [
Passive Hip Exosuit Design. ( | PMC10339586 |
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Data analysis and processing | SECONDARY | We completed initial kinematic and kinetic data processing in Visual 3D (C-Motion Inc., Germantown, MD). Data was filtered in Visual 3D using a fourth-order low-pass Butterworth filter with a 6 Hz cutoff frequency. We exported ground reaction forces (GRF) and heel marker locations to MATLAB. Using a custom script, we used GRF data to detect the left and right heel contact and toe-off times of each trial. We subtracted the initial heel contact time from the next heel contact time on the same side for both the left and right sides to calculate stride time. Our primary outcome was step length symmetry index, and our secondary outcomes were stance time and swing time symmetry. We calculated step length as the anterior-posterior distance between the leading leg heel marker and the trailing leg heel marker at heel contact of the leading leg in accordance with previous studies [where F stands for the leg on the fast belt or the leg that was not resisted by the exosuit, and S stands for the leg on the slow belt or leg that was resisted by the exosuit brace. Values of zero represent complete symmetry. Larger negative or positive values represent asymmetries between legs. | PMC10339586 |
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Statistical analysis | For our statistical analysis, we compared the average step length, stance, and swing time SI values at five different time points: baseline (BL), early adaptation (EA), late adaptation (LA), early post-adaptation (EP), and late post-adaptation (LP). BL, LA, and LP correspond to the average SI values during the last ten strides of baseline, the final adaptation trial, and the tenth minute of post-adaptation, respectively. EA and EP refer to the first ten strides of the adaptation and post-adaptation periods. We checked the normality of all dependent variables using a Shapiro-Wilk test. Data was considered as an outlier if the value was more than two standard deviations away from the group mean. To assess SI differences between and within groups at the specified time points, we implemented a 3 × 5 mixed ANOVA. Significant between-group interactions underwent follow-up simple effects tests using one-way ANOVAs. We used follow-up one-way repeated measures ANOVAs and paired comparisons to determine specific within-group time point differences. We set the significance threshold at p < 0.05 with a Bonferroni correction for simple comparison tests. The researchers and the participants were not blinded for this initial study. | PMC10339586 |
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Results | PMC10339586 |
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Demographics and outlier verification | We found no differences in height (F = 0.026, p = 0.974) and weight (F = 0.290, p = 0.753) among the three experimental groups. One participant from Exo-Sb had a step length symmetry index at EP over two standard deviations from the group mean. We considered this participant an outlier and removed him from the step-length SI analysis. There were no other outliers. We report Huynh-Feldt corrected p-values for models that did not pass Mauchly’s Test of Sphericity. | PMC10339586 |
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Temporal gait asymmetry is unaffected by the unilateral hip exosuit | For stance time SI, we found a significant interaction between group and time with a large effect size (F = 9.47, p-corrected = 0.00014, ηSimilar findings were seen for the swing time SI (Fig.
The Passive Exosuit Does Not Alter Induced Temporal Asymmetry. Panel A displays Exo-only (red), Exo-Sb (green), and Sb-only (blue) stance time SI values and Panel B displays swing time SI values for the same groups at baseline (BL), early adaptation (EA), late adaptation (LA), early post-adaptation (EP), and late post-adaptation (LP). The “*” marks significant differences between groups at specific timepointsFollow-up tests were run on all three groups for stance and swing time SI. We discovered no differences between timepoints for Exo-only (F = 01.22, p-corrected = 0.3412, η | PMC10339586 |
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Between group step length asymmetry differences persist at early adaptation and early post-adaptation | We found an interaction between group and time with a large effect size for step length SI (F = 29.55, p-corrected < 0.0001, η
Between-Group Step Length SI Differences Persist. Step length SI values for Exo-only (red), Exo-Sb (green), and Sb-only (blue) at baseline (BL), early adaptation (EA), late adaptation (LA), early post-adaptation (EP), and late post-adaptation (LP). The “*” marks significant differences between groups at specific timepoints. Exo-only produced changes in the opposite direction as split-belt conditions which may explain the difference between Exo-Sb and Sb-only at EP | PMC10339586 |
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A unilateral hip exosuit diminished within-group step length asymmetry post-effects | We ran one-way repeated measure ANOVAs on each group to assess the effect of individual perturbations on step length asymmetry (Table
Step Length SI Group Means and SD Across Time PointsPPPP-values from mixed-model ANOVA; BL: Baseline, EA: Early-adaptation, LA: Late-adaptation, EP: Early Post-adaptation, LP: Late Post-adaptation, Exo-only: Exosuit-only, Sb-only: Split-belt only, Ex-Sb: Combined Exosuit and Split-belt, SD: Standard Deviation* Represents values < 0.05Exo-only had differences in step length SI across timepoints (F = 10.20, p = 0.0003, ηDifferences in step length SI values across time points with a large effect size were found for Exo-Sb (F = 19.84, p < 0.0001, η2 = 0.814). Follow-up paired comparisons determined that Exo-Sb produced larger negative step length SI values at EA compared to BL (p = 0.0014), LA (p = 0.0031), EP (p < 0.0001), and LP (p = 0.0004). At EP, Exo-Sb was found to have larger positive step length SI values compared to LA (p = 0.0357) but not to BL (p = 0.0885) (Additional File
The Passive Hip Exosuit Diminishes Mean Step Length Asymmetry During Post-Adaptation. Panel | PMC10339586 |
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Discussion | stroke | STROKE, RECRUITMENT | This study investigated how a passive unilateral hip exosuit modified the temporal and spatial gait characteristics of healthy individuals with induced walking asymmetry (i.e., split-belt treadmill walking). We hypothesized that wearing the passive unilateral hip exosuit while walking on a split-belt treadmill would diminish induced asymmetry from the split-belt during the initial adaptation trial and after the belts returned to a tied configuration. The experimental results from this study partially support our hypothesis.In healthy individuals, we found that combining the exosuit with split-belt walking (i.e., Exo-Sb) did not change the step length asymmetry during EA compared to participants in Sb-only. Additionally, the results indicated that the passive hip exosuit did not mitigate any temporal (i.e., stance and swing time) asymmetries while walking on the split-belt treadmill. However, in support of our hypothesis, results showed that combining the exosuit with split-belt walking (Exo-Sb) diminished the within-group step length asymmetry after-effect when treadmill belts returned to the same velocity at the start of the post-adaptation period.Previous studies in healthy participants found that temporal parameters, such as stance and swing time, changed immediately with the introduction of a split-belt perturbation [The initial change in velocity at EA resulted in larger negative step length asymmetries for participants in Sb-only and Exo-Sb conditions (i.e., the leg on the fast-belt or the non-dominant leg took shorter steps compared to the leg on the slow belt or the dominant leg), again similar to previous studies examining the split-belt paradigm [The removal of each of the perturbations resulted in a significant within-group step length symmetry post-effect in participants from Sb-only, suggesting that the addition of the exosuit diminished within-group step length symmetry post-effects in participants from Exo-Sb. The removal of the exosuit led participants in Exo-only to walk with negative step length asymmetry values at EP (i.e., the leg that experienced the passive exosuit resistance took larger steps compared to the non-dominant limb), however, the effect of the exosuit was not strong enough to result in a significant post-effect between EP and BL. This is similar to recent results with a powered unilateral exosuit that produced a post-effect that was apparent in the mean but not significant [In line with previous literature, the interlimb symmetry results from this study confirm that passive exosuits have the potential to alter gait characteristics [The finding that it is possible to diminish induced step length asymmetry after-effects in healthy participants using a simple, lightweight design supports interest in future studies in patient populations with asymmetric gait. Recently, however, research has questioned whether diminishing gait asymmetry helps to improve gait in patients with hemiparesis. Musculoskeletal models, as well as experiments involving participants following stroke, found that acutely restoring step length symmetry did not improve the metabolic cost of transport and may even negatively impact dynamic balance in patient populations [Although improving symmetry would seem to improve walking ability, it has been shown that after several weeks of training, gait asymmetry did not change [This study had some methodological limitations. The participant recruitment for this experiment occurred through convenience sampling on a college campus. Despite the recruitment age range from 19 to 40 years old, the sample selected may not generalize to the entire population. Additionally, healthy young adults volunteered as participants for this investigation, and the findings herein may not relate to clinical populations. We tested the effect of the device when it was attached to the limb on the slow belt only. The impact of the device could change if we placed it on the limb on the fast belt. Depending on an individual’s size or movement, the positioning of the exosuit could have changed during the trial leading to errors when calculating the force of the band. We did not evaluate qualitative measures of the passive exosuit like comfort, fit, and aesthetics. Future investigations should evaluate these qualitative measures in patient populations to encourage adherence to a training protocol. Due to the scope of the present study, we have not yet processed a sufficiently large number of strides to investigate aspects such as variability and changes in relative phasing over time that inform how participants adapt to different attractors. Future research may benefit from applying analysis techniques from Dynamical Systems Theory to understand how the device impacts coordination patterns throughout the entirety of data collection. | PMC10339586 |
Conclusions | Our study found that wearing a unilateral passive hip exosuit while walking on a split-belt treadmill led to diminished step length asymmetry once the belts return to a tied configuration. The simple design suggests that practical, inexpensive devices can alter walking patterns in healthy individuals. The results from this study warrant future research investigating different band configuration setups, walking with the device for extended periods overground, as well as testing in patient populations walking with asymmetric stepping patterns. Determining the long-term potential of such devices could improve therapeutic interventions for patient populations and offers the opportunity for widespread accessible interventions. | PMC10339586 |
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Acknowledgements | The authors would like to thank Alex Dzewaltowski for his help on the MATLAB code. | PMC10339586 |
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Authors’ contributions | MM | KK: conception, design, acquisition, analysis, interpretation, drafting, revision; MM: design, analysis, revision; PM: conception, design, analysis, interpretation, revision. | PMC10339586 |
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Funding | This research was supported by funding from the Graduate Research and Creative Activity Grant (GRACA) from the University of Nebraska at Omaha, NIH P20GM109090, an AHA AIREA award (#959486) and a NU Collaboration Initiative grant. P.M. also received partial support from the NSF (2203143). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, AHA or NSF. | PMC10339586 |
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Data Availability | All data generated or analyzed during this study are included in this published article [and its supplementary information files]. | PMC10339586 |
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Declarations | PMC10339586 |
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Ethics approval and consent to participate | The Institutional Review Board at the University of Nebraska Medical Center approved this study. Participants read and signed informed consent forms before filling out the health-history questionnaire. | PMC10339586 |
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Consent for publication | A consent form for a cover photo was signed by the individual in the photo. | PMC10339586 |
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Competing interests | An application for a provisional patent describing “Asymmetric Hip Brace” has been submitted by KK and PM (serial number 63/325,922; docket number 22025P, filed on March 31, 2022). | PMC10339586 |
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Authors’ information | KK currently holds a doctoral research assistantship position in the Mary Frances Early College of Education’s Department of Kinesiology’s Concussion Research Laboratory at the University of Georgia. | PMC10339586 |
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Abbreviations | Central nervous SystemConstraint-Induced Movement TherapyGround Reaction ForceExosuit Only GroupSplit-belt Only GroupSimultaneous GroupAnalysis of VarianceBaselineEarly AdaptationLate AdaptationEarly Post-adaptationLate Post-adaptationSymmetry Index | PMC10339586 |
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References | PMC10339586 |
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Purpose | obesity, satiety | OBESITY | Early satiety has been identified as one of the mechanisms that may explain the beneficial effects of nuts for reducing obesity. This study compared postprandial changes in appetite-regulating hormones and self-reported appetite ratings after consuming almonds (AL, 15% of energy requirement) or an isocaloric carbohydrate-rich snack bar (SB). | PMC9614749 |
Methods | overweight | OBESE | This is a sub-analysis of baseline assessments of a larger parallel-arm randomised controlled trial in overweight and obese (Body Mass Index 27.5–34.9 kg/m | PMC9614749 |
Results | Postprandial C-peptide area under the curve (AUC) response was 47% smaller with AL compared to SB ( | PMC9614749 |
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Conclusion | More favourable appetite-regulating hormone responses to AL did not translate into better self-reported appetite or reduced short-term energy consumption. Future studies should investigate implications for longer term appetite regulation. | PMC9614749 |
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ANZCTR Reference Number | ACTRN12618001861246 | ACTRN12618001861246 2018. | PMC9614749 |
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Supplementary Information | The online version contains supplementary material available at 10.1007/s00394-022-03027-2. | PMC9614749 |
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Keywords | Open Access funding enabled and organized by CAUL and its Member Institutions | PMC9614749 |
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Introduction | obesity | OBESITY | The high prevalence of overweight and obesity is a major public health concern [Epidemiological studies have provided evidence that regular consumption of nuts may reduce the risk of obesity [It has been suggested that humans compensate for the energy from nuts by reducing intake of other foods at subsequent eating occasions [Adaptive responses resulting from nut consumption may reflect effects on hormones involved in appetite control [The purpose of this study was to compare the effects of eating almonds or a carbohydrate-based snack on appetite-regulating hormones, self-reported appetite ratings, and short-term energy intake. We hypothesised that almonds would have favourable effects on appetite-regulating hormones and self-reported appetite ratings, reducing subsequent energy intake compared to the carbohydrate-based snack, and thus providing insight into the association of nut consumption with a reduced risk of obesity. | PMC9614749 |
Materials and methods | PMC9614749 |
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Ethics approvals and trial registration | Ethics approval was obtained from the University of South Australia Human Research Ethics Committee (201,436) and the trial was registered with the Australian and New Zealand Clinical Trials Registry (ATCRN12618001861246). | PMC9614749 |
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Study setting, design and participants | weight loss | Data reported here were obtained from a parallel-arm randomised controlled trial that was conducted between January 15, 2019 and March 10, 2021 in the research facilities of the Alliance for Research in Exercise, Nutrition and Activity Centre (ARENA) at the University of South Australia, Adelaide. Written informed consent was obtained from participants prior to participation. The intervention trial examined whether the inclusion of almonds or carbohydrate-rich snacks in an otherwise nut-free energy-restricted diet would promote weight loss and protect against weight regain. Energy requirements were calculated using the Schofield equation and physical activity captured via the International Physical Activity Questionnaire [ | PMC9614749 |
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Eligibility, randomisation and allocation | Participants were males and females, aged 25–65 years, weight stable, non-smokers, with a BMI of 27.5–34.9 kg/m | PMC9614749 |
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Appetite assessments | appetite sensations | Participants attended the clinic following an overnight fast (> 10 h). Baseline blood samples were taken using an antecubital vein catheter, after which participants consumed their randomly allocated snack (almonds or a carbohydrate-based snack) with 200 mls of water within a 10-min period. Repeat blood sampling (via canulation) was performed every 30 min post snack for 2 h. Water (200 mls) was given at 60 min, and 100 mls at 90 min after snack consumption. Immediately after each blood draw, protease inhibitors (Sigma P2714 and Millipore DPP4-010) were added to the specimen tube. All samples were stored as serum at − 80 °C until assayed in duplicate. Appetite hormones ghrelin, GIP, GLP-1, leptin, PP, PYY as well as C-peptide and glucagon were assessed using a multiplex analysis system (LUMINEX MAGPIX, Millipore, Merck). CCK was assessed using ELISA (Ray Biotech). All samples for the same participant were run in the same assay.Participants were asked to rate their subjective appetite sensations by answering four questions at the time of each blood draw. Each question was answered using a visual analogue scale (VAS); a 10 cm horizontal line anchored at both ends so that answers could be indicated on a continuous scale. VAS for appetite assessment has been shown to have good validity, reliability, and reproducibility [ | PMC9614749 |
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Meal challenge buffet | In a sub-set of participants, a buffet meal was provided 2 h after test food consumption. The number of participants who consumed the buffet was limited due to the impact of COVID-19 lockdowns. Participants were given 30 min to eat as much or as little as they liked. The buffet was nut-free and provided a selection of core and discretionary foods and beverages, as defined by the Australia Dietary Guidelines, in generous volumes, and with limited predefined units (See supplementary Table 2 for a list of buffet foods). Food consumed (weighed before and after) was assessed for total energy via Foodworks Nutritional Analysis Software V.9 (Xyris Software, Brisbane, Queensland, Australia). A final set of VAS were performed immediately post buffet at 150 min. | PMC9614749 |
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Statistics | All statistical analyses were performed using the SPSS for Windows V.24.0. (SPSS, Inc., Chicago, IL, USA). Sample size calculations were based on the primary outcome (change in weight) from the larger study and are detailed in the protocol paper [ | PMC9614749 |
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Results | PMC9614749 |
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Participant flow and baseline characteristics | A total of 140 participants completed the assessments (Male = 42, Female = 98, Age 47.5 ± 10.8 years, BMI 30.7 ± 2.3 kg/mConsort flow diagramParticipant baseline characteristicsAll | PMC9614749 |
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Appetite-regulating hormones | SE | C-peptide AUC response was significantly smaller in AL compared to SB (46.9%, Mean AUC for appetite hormonesCholecystokinin C-peptide, Glucagon, Glucose-dependent Insulinotropic Polypeptide (GIP) and Pancreatic Polypeptide (PP) Concentrations. Mean ± SE timepoint comparison * The AL GIP AUC response was significantly larger than the response for SB (17.8%, The AL glucagon AUC response was significantly larger than the response for SB (38.7%, PP AUC response was significantly larger in AL compared to SB (44.5%, AUC for CCK, ghrelin, GLP-1, leptin and PYY did not differ between groups. Timepoint comparisons indicated a higher GLP-1 concentration at 60 ( | PMC9614749 |
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Subjective appetite ratings | SE, fullness, appetite sensations | There was no evidence of a difference in self-reported appetite sensations (feelings of hunger, fullness, satisfaction and prospective food consumption [prospective eating]), obtained via VAS, to the different test snacks. In both groups, hunger and prospective eating decreased post snack and steadily increased over the remainder of the testing period. Similarly, fullness and satisfaction increased in both groups post snack and decreased over the remainder of the testing period (Fig. Self-reported appetite sensations measured using VAS. Mean ± SE timepoint comparison. Almond, | PMC9614749 |
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