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Assessment of the clinical significance of the pharmacy interventions proposed to mitigate MRPs.
PMC10602279
Discussion
MIH
The current study showed that patients discharged from hospital in general expressed a high level of satisfaction with the standard care medicine information provided by the health care personnel at the wards during hospitalization and at discharge. Despite this, a number of patients still had questions regarding their medication after hospital discharge. As expected, the rate of patients who had a question regarding their medicines was higher in the group of patients who reported having experienced a change in their medication during hospitalization indication that changes in medicine may lead to insecurity. Patients who were offered access to contact a newly established hospital-based MIH reported an increase in their feeling of safety in relation to their medication and all patients in contact with the MIH were “to a great extent” satisfied with the MIH service. However, asking all patients about their perception of safety in relation to medicines use revealed no difference between the control and the intervention group. During the study period, a total of 37 enquiries were received and answered. Analysis of the enquiries revealed 43 MRPs of which 53% triggered interventions assessed to have a moderate to high clinical significance.
PMC10602279
Need for medicine information after discharge
The present study shows that approximately one fourth of the participants (26%) express a needed for information about their medication after hospital discharge. Similar results have been reported by Shuen et al. who found that 26% of patients discharged from an emergency department made a call or visit to their primary medical doctor or a specialist physician post discharge [
PMC10602279
Increased patient safety
MIH
Analysis of the patient enquiries to the MIH revealed that 53% triggered interventions assessed to have a moderate to high clinical significance, suggesting that the interventions improved the patient safety of the patient medication. It is well known that medication after discharge is indeed a major cause of rehospitalization [
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High level of patient satisfaction with MIH
MIH
This study showed a high level of satisfaction with the MIH. The participants found the answers to their enquiries comprehensible and relevant, which affected their use of medicine. Other medicine helplines have reported similar high ratings of user satisfaction where the majority of the patients report that they received sufficient information and felt reassured about their medicine [In this study, the most common enquiries were related to dose, administration, effect and usage of medicines. The nature of these enquiries is similar to those found in the literature [
PMC10602279
Perception of safety with medicine after discharge
MIH
Patients in both groups reported that they to a high degree felt safe with their medication after discharge. Further, the current study revealed that patients with access to the MIH expressed an increase in the feeling of safety in relation to their medication; see Relevant medical information not only enables the patients to prevent and solve MRPs, but it may also be a key factor in relation to medicine adherence [
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Methodological considerations
The present study was using a randomized study design. The dropout rate (enrolled patients not performing the telephone interview) in the current study was higher than anticipated (39%, 17 and 81 in the control and intervention group respectively) limiting the power to identify statistically significant differences. Applicable to both groups, the high dropout rate was mainly due to patients not answering their phone or being readmitted. For future studies, a suggestion to minimize the high dropout rate could be to schedule follow-up telephone calls or to arrange a personal meeting in the patients’ private homes and enroll patients who are less prone to be readmitted.Another limitation in the current study concerns the interview guide that includes some questions that are not fully validated. However, most of the questions in the interview guide were adopted word-for-word from other studies ensuring that the majority of the questions had been tested by other researchers beforehand [The clinical impact of the helpline responses was assessed by two clinical pharmacists working at the MIC. This is a potential bias, and it would have strengthened the data analysis if an impartial party had analyzed the responses.Another methodological consideration in the current study is the risk of respondent’s social desirability bias where respondents may respond in a way they think the investigator wants to hear and hereby present themselves in the best possible way [Further, there is a risk of recall bias, which is a systematic error that occurs when the participants do not recall or remember previous experiences accurately or omit details related to the topic of interest [Participants in the current study were included from two departments, an emergency department and a department of respiratory medicine. Thus, the present results are most probably only representative of similar clinical settings. Indeed, future studies should investigate other clinical settings.
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Conclusion
MIH
MIH offers support for discharged patients to alleviate MRPs. More than 50% of the MRPs found in this study resulted in pharmacy interventions assessed to have a high- or moderate clinical significance. Although patients expressed a high satisfaction with the MIH, the access to the MIH did not significantly increase patients’ feeling of safety in relation to medicines use. This study emphasizes that patients value the service and the information provided by the MIH, and that the service might positively affect a safe medication after discharge. Changes in the medical treatment after discharge is challenging and patients should be provided with sufficient pharmaceutical support and information to overcome these struggles, ultimately ensuring a patient safe medication.
PMC10602279
Supporting information
PMC10602279
CONSORT 2010 checklist of information to include when reporting a randomised trial*.
(DOC)Click here for additional data file.
PMC10602279
This is the interview guide.
(DOCX)Click here for additional data file.
PMC10602279
This is the results based in the interview guide.
(DOCX)Click here for additional data file.
PMC10602279
This is the ethic committee protocol in Danish.
(DOCX)Click here for additional data file.
PMC10602279
This is the ethic committee protocol in English.
(DOCX)Click here for additional data file.
PMC10602279
This is the raw data from the case handling of request to MIH.
(DOCX)Click here for additional data file.
PMC10602279
This shows means, medians and box plots for all data given in ordinal variables.
(DOCX)Click here for additional data file.
PMC10602279
1. Introduction
fracture, skeletal disorder, osteoporosis, osteopenia
SKELETAL DISORDER, FRAGILITY, OSTEOPENIA, ESTROGEN DEFICIENCY, OSTEOPOROSIS, OSTEOPOROSIS
Estrogen deficiency increases the risk of osteoporosis and fracture. The aim of this study was to investigate whether a hop extract standardized in 8-prenylnaringenin (8-PN), a potent phytoestrogen, could improve bone status of osteopenic women and to explore the gut microbiome roles in this effect. In this double-blind, placebo-controlled, randomized trial, 100 postmenopausal, osteopenic women were supplemented with calcium and vitamin D3 (CaD) tablets and either a hop extract (HE) standardized in 8-PN (Osteoporosis is a skeletal disorder characterized by reduced bone mass and deterioration in bone architecture leading to increased bone fragility and fracture risk [As a novel phytoestrogen, 8-PN is unique in that its receptor specificity and potency is higher than any other phytoestrogens investigated thus far [While the presence of 8-PN in hops is low, other more abundant prenylated phenols such as xanthohumol (X) and isoxanthohumol (IX) can be metabolically converted to 8-PN. The conversion of IX into 8-PN can be accomplished enzymatically by hepatic CYP1A2 or by the gut microbiome [The present clinical trial aimed to determine whether one-year consumption of a hop extract standardized in 8-PN can moderate bone mineral density decreases in postmenopausal women with osteopenia and to explore potential mechanism of action via gut microbiome modulation.
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2. Materials and Methods
PMC10304064
2.1. Study Design and Participants
RECRUITMENT
This study was a 48-week, parallel-design, placebo-controlled, double-blind, randomized clinical trial. The clinical aspects of the study were carried out from August 2019 to December 2020 in Cork (Ireland), including screening, recruitment, and follow-up. Participants were recruited through advertisements (local newspaper and social media platforms) or referred by local general practitioners in the area. A total of 221 participants were screened to identify 100 eligible participants, all of whom were postmenopausal women (>1-year post-menopause), between 50 and 85 years of age, with a body mass index (BMI) between 18–32 kg/mParticipants who gave written informed consent and were deemed eligible at their screening visit were assigned a randomization number in chronological order. The randomization list was generated by an independent biostatistician (Atlanstat, France). A permuted-block, fixed randomization schedule was used with 2 block sizes (the first 14 blocks were size 6 and the next 14 blocks size 4), based on a computer-generated random numbers program (SASRandomized participants were scheduled to attend 5 visits at the research center at baseline (0), 12, 24, 36, and 48 weeks. Anthropometric parameters (height, weight, BMI, waist circumference, and hip circumference), vitals (blood pressure, heart rate, and temperature), quality of life assessed by the 36-item short form (SF-36), and physical activity assessed by the Physical Activity Scale for the Elderly (PASE) were measured at each visit. DXA measurements (BMD at femoral neck, L2–L4, total hip and total body, T-score at femoral neck and L2–L4, FRAX scores and body composition), fecal samples, and blood samples were collected at baseline, at 24 weeks, and at 48 weeks, while urine samples and dietary intake assessed by the food frequency questionnaire (FFQ) were collected at baseline and at 48 weeks only. Due to the COVID-19 pandemic and Irish government restrictions, it was not possible to conduct interim visits (weeks 12, 24, and 36) at the research center. Notably, DXA, anthropometric, and laboratory assessments were either collected on site later or were unable to be collected at these interim visits. The research was conducted under guidelines stated in the current revision of the Declaration of Helsinki, was approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals, and was registered at
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2.2. Study Product
Hop extract (HE) standardized in 8-PN (Lifenol
PMC10304064
2.3. Bone Measurements by Dual-Energy X ray Absorptiometry
Fracture
Body composition was assessed with DXA. DXA examination, performed by the same health care professionals each visit, was conducted using the Lunar iDXA ME +210575 (GE Healthcare, Chicago, IL, USA). DXA was used to determine bone mineral density (BMD) and T score at each body site; DXA was also used to determine body composition (lean mass, fat mass, visceral fat, and fat percentage). Fracture risk assessment was determined using the FRAX tool (
PMC10304064
2.4. Biomarkers of Bone Turnover and Biochemical Analysis
Fasting blood samples collected in EDTA/heparin tubes were centrifuged at 3000 rpm at 4 °C for 10 min within 40 min after collection. Samples were stored at −80 °C until analysis. Plasma concentrations of osteocalcin and sclerostin were measured using an automated analyzer according to the manufacturer’s instructions (Multiplex LuminexSerum 25- hydroxyvitamin D (25-OH D3), plasma 17-β oestradiol, blood lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides), glucose homeostasis parameters (blood glucose, insulinaemia, HbA1c, and HOMA IR), and safety parameters were also measured.
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2.5. Plasma and Urine Prenylflavonoids and Their Metabolites
6-PN
All prenylflavonoids (X, IX, 6-PN, and 8-PN) were measured both in plasma and urine in their unconjugated, glucuronide, and sulfated forms; each were expressed as a sum of the 3 different forms (i.e., total). Standard of X (purity: 99.6%), IX (purity: 99.6%), 8-PN (purity: 100%), and 6-PN (purity: 97%) were purchased from Phytolab (Vestenbergsgreuth, Germany). β-Glucuronidase enzyme from Urine and plasma samples were stored at −80 °C until analysis; they were then prepared with an automated workstation (Beckman Coulter, Biomek NX, Brea, CA, USA) in random order. For the plasma samples, 100 µL of plasma or enzymatic hydrolyzed plasma were loaded on Captiva EMR-lipid plate (Agilent Technologies, Santa Clara, CA, USA). An amount of 300 µL of MeOH/ACN (50:50) were added and mixed at 700 rpm for 3 min. Samples were then eluted by positive pressure. An amount of 100 µL of MeOH/ACN (50:50) were loaded on the cartridge once again and eluted by positive pressure. For the urine samples, 300 µL of water were loaded on Captiva ND plate, and 100 µL of urine or enzymatic hydrolyzed urine were added and mixed at 700 rpm for 1 min. Samples were then eluted by positive pressure and analyzed by LC-HRMS. Enzymatic hydrolyzed urine and plasma samples were prepared with 10 mg of enzyme diluted in 10 mL sodium phosphate buffer (100 mM, pH = 6.8) for β-Glucuronidase and in 10 mL sodium acetate buffer (100 mM, pH = 5) for sulfatase enzyme. An amount of 60 µL of this solution were mixed with 60 µL of plasma or urine and incubated during 1 h at 37 °C. Noting the difference between the concentrations measured before and after enzymatic hydrolysis provides the ability to calculate the concentrations of the glucuronide/sulfated forms. Liquid chromatography was performed on a UHPLC Thermo Vanquish (Thermo Scientific, Karlsruhe, Germany) in reverse phase mode with an Accucore RP-MS column (150 × 2.1 mm, 2.6 µm, Thermo Scientific) using solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in ACN). The elution gradient started at 5% B for 1 min, followed by a linear gradient rising to 90% B during 9 min. The mobile phase remained at 90% B for 5 min and then returned to initial condition after 1 min. The column was equilibrated for 4 min in initial conditions (5% B) prior to the next injection, for a total run time of 20 min. The flow rate was 0.5 mL/min, and the injection volume was 2 µL. The column was heated at 30 °C to ensure a stable column temperature and a better repeatability between runs, and the autosampler temperature was maintained at 6°C. The UHPLC system was coupled to an Orbitrap Q-Exactive Focus mass spectrometer (Thermo Scientific, Germany), and analyses were performed using an electrospray interface in negative mode, in full scan with a resolution of 35,000 FWHM in the scan range of This analytical method was validated according to internal guidelines and specificity, linearity, repeatability, and limit of quantification (LOQ) are listed in
PMC10304064
2.6. Dietary Intake, and Physical Activity Level, and Quality of Life
Dietary habits, using the EPIC-Norfolk Food Frequency Questionnaire (FFQ; Physical activity level was registered using the self-reported level of Physical Activity Scale for the Elderly (PASE) [Health-related quality of life was measured by measuring the means scores of the Short Form 36 (SF-36) [
PMC10304064
2.7. Gut Microbiome Analysis
PMC10304064
2.7.1. Fecal Samples Collection and DNA Extraction
LYSIS
Fecal samples were collected at baseline, at 24 weeks, and at 48 weeks. Participants were provided stool collection kits and instructed to collect an at-home sample within 48 h of their next research visit. The fecal sample was collected using a collection vial and then placed immediately in the home freezer (−20 °C) before being brought to the clinic in a provided cooler bag with a cooler block. Samples received at the research center were immediately placed in a freezer at −80 °C.Genomic DNA was extracted using the ZymoBIOMICS™ 96 MagBead DNA kit (Zymo Research Corp., Irvine, CA, USA) integrating a double lysis (mechanical and chemical) on the Precellys Evolution homogenizer (Bertin Instruments, Montigny-le-Bretonneux, France). DNA extraction was performed on the KingFisher Flex automaton (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions. Once obtained, the DNA solutions were assayed by fluorimetry with the Qubit device (Thermo Fisher Scientific, Waltham, MA, USA).
PMC10304064
2.7.2. Libraries Preparation and Shotgun Metagenomic Sequencing
Fragmentation of the extracted total DNA was performed using the FS DNA Library Prep Set kit (MGI Tech, Shenzhen, China). After ligation of adapters to each sample, the libraries generated were purified on magnetic beads. Library size was verified by capillary electrophoresis on at least 10% of samples. After quantification by fluorimetry, the libraries were normalized and pooled before denaturation, single-strand circularization, and sequencing using the DNBSEQ-G400 platform (MGI Tech).
PMC10304064
2.7.3. Analysis of Overall Association and Taxonomic Profile
fits, MiRKAT
REGRESSION
The MiRKAT family of tests was used to assess overall association between taxonomic compositional profiles and treatment group [Assessment of microbiota components showing differential abundance between treatment groups was evaluated using CoDA-lasso enriched with stability analysis. CoDA-lasso is a multivariate approach that fits a regularized logistic regression model with an additional constraint on the regression coefficient due to the compositional nature of relative abundance data [The relevance of each selected taxon to discriminate between the treatment groups was investigated assessing variable importance in prediction with random forests. Each random forest comprised 500 non-pruned classification trees. Reported results comprised the selected taxa sorted according to their relative relevance in prediction, a sample estimate of the log-fold difference between the mean abundance of each group, and a heatmap of the taxa prevalence in each compared group.
PMC10304064
2.7.4. Quantification of SCFA
For the quantification of short-chain fatty acids (SCFA), fecal samples were divided in two aliquots, one for the lyophilization, and the second for a direct measure of the molecules of interest in order to obtain the dry weight-normalized absolute concentration. SCFA (acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, isobutyric acid, isovaleric acid, and isocaproic acid) were measured on the second aliquot of test material via a gas chromatography–flame ionization detector (GC-FID) method as described by De Weirdt et al. [
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2.8. Compliance and Adverse Events
death, TEAE
EVENTS
Participants were asked to collect and return empty IP and CaD supplement containers at each visit. Compliance was calculated from the number of IP and CaD supplements returned. Compliance for both IP and CaD was calculated, in percentage, as: (100 × total number of capsules administered)/(theoretical number of capsules per day × extent of exposure in days) at each individual visit and for the entire study period. Participants were considered non-compliant for the IP if they had (1) an overall IP compliance <80% or >120%, or (2) an overall compliance within [80%; 120%], but at least one individual visit IP compliance <70% or >130%, or (3) an overall IP compliance missing and less than three available individual visit IP compliances within [80%; 120%].Adverse events (AEs) were collected on AE forms throughout the trial. AEs were considered as treatment emergent (TEAE) if they began or worsened from the date of the first IP administration. AEs were recorded in the eCRF at each visit; recordings included a description of the AE, the relationship to the intervention (“not related” or “related or suspected”), whether the AE was serious (i.e., resulted in death, life-threatening, required hospitalization, or resulted in persistent disability) or nonserious, and the intensity of the AE (mild, moderate, severe).
PMC10304064
2.9. Power Calculation and Statistical Analysis
L2-L4 lumbar spine region
SECONDARY
The sample size was calculated to detect a difference in the change from baseline to 48 weeks in BMD measured by DXA on the L2-L4 lumbar spine region between HE and placebo (primary outcome) with consideration of the findings from previous studies [Data were analyzed using SASThe primary outcome, and all other DXA parameters, were analyzed using an analysis of covariance (ANCOVA) including analysis group, baseline values, time since menopause at screening (months), and BMI at baseline (kg/mFor bone biomarkers, the changes from baseline in each parameter were analyzed at week 48 using a mixed model for repeated measures (MMRM), including the following covariates, in addition to analysis group and baseline value: time since menopause at screening and BMI at baseline. Comparisons within and between groups were studied. Regarding the other secondary and exploratory outcomes, depending on planned time points, an ANCOVA at week 48 including analysis group and baseline value or a MMRM including analysis group, visit, baseline values, and group*visit interaction was performed.For all analyses, normality distribution of the residuals was verified by Skewness and Kurtosis. If the adequacy of the model could not be validated, the parameter was derived using the log transformation of the values at each time point and was then modeled with the same model characteristics. If the adequacy of the new model was not able to be validated on the log transformation, a non-parametric analysis of covariance, based on ranks (rank ANCOVA) with the same covariates was performed for the comparison between groups and Wilcoxon signed-rank test for the comparison within group.Regarding safety, all analyses were performed on all participants who received at least one dose of study treatment according to the analysis groups. The incidence of AEs was assessed, and a description according to SOC and PT was tabulated. The number of patients with at least one TEAE was compared between analysis groups using a chi-squared test. Normal data were reported as means ± SD and non-normal data as median (Q1; Q3). All statistical tests were conducted two-sided with a significance level of 5%. No adjustment for multiplicity was considered.
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3. Results
PMC10304064
3.1. Baseline Characteristics of the Study Population
A total of 221 women were screened, among whom 100 were deemed eligible and assigned randomly to HE (Baseline data of the FAS population are presented in
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3.2. Safety and Compliance to the Intervention
6-PN
Participant compliance to the IP was good with only 17% and 13% of participants who were non-compliant in the HE and placebo groups respectively. Similarly, compliance of the CaD supplements was good with only 11% and 4% of participants consuming <80% or >120% of the supplements in the HE and placebo group, respectively. Both HE and placebo capsules were well tolerated.Analysis of the prenylflavonoids concentrations in urine and plasma confirmed the good adherence to the treatment. Indeed, X, IX, 6-PN, 8-PN, and their metabolites (glucuronide and sulfated forms) were present after 48 weeks in both urine and plasma of the HE group, while absent or negligible in the placebo group. In urine samples from the HE group, total 8-PN was detected in 94% of the participants with a mean concentration of 13.96 ± 19.11 ng/mL; total 8-PN was detected in 76% of participant plasma samples of the HE group at a mean concentration of 1.09 ± 0.92 ng/mL (Regarding safety, there were a total of 127 TEAEs reported during the trial, of which 55 were noted in the HE group and 77 in the placebo group (
PMC10304064
3.3. DXA Parameters
L2-L4 lumbar spine
For the primary outcome, mean change in BMD at L2-L4 lumbar spine, from baseline after 48 weeks, revealed a slight but not statistically significant increase in the HE group (0.0063 ± 0.0371 g/cmAmong the other DXA parameters, there was a significant increase in the total body BMD within the HE group at week 48 compared to baseline (0.0180 ± 0.0302 g/cmRegarding body composition, lean mass and fat percentage were not modulated in any groups, while fat mass and visceral fat were significantly increased after 48 weeks compared to baseline in the HE group (median change (Q1; Q3) = 714.0 (−123.0; 1285.0) g for fat mass and 52.5 (−55.0; 213.0) g for visceral fat, Additionally, post hoc sub-group analysis was performed according to vitamin D status (sufficient if ≥75 nmol/L and insufficient if <75 nmol/L). In vitamin D sufficient women, there was an increase in the HE group compared to the placebo group for the BMD at L2-L4 lumbar spine (difference of adjusted relative changes from baseline ± SE = 2.29 ± 1.16%;
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3.4. Biochemical Analysis
No significant differences were observed between the HE and placebo groups after 48 weeks of supplementation for any of the plasma bone biomarkers measured (Similarly, no significant differences between groups were observed at 48 weeks for the following blood parameters: triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol, fasting glucose, insulinemia, HbA1c, HOMA-IR, serum 25-OH D3 concentration, and 17-β oestradiol (
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3.5. Antropometrics, Physical Activity, Dietary Intake and Health-Related Quality of Life
No significant differences between groups were observed for anthropometric parameters at any visit (Dietary analysis using the FFQ showed both groups had similar intake at baseline. After 48 weeks, the HE group showed higher fat, calcium, and vitamin KChanges in SF-36 scores after 48 weeks are shown in
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3.6. Gut Microbiome Modulation
MiRKAT
As the gut microbiota is a key player in prenylflavonoid metabolism and bone homeostasis, potential differences in the microbiome composition between the HE and placebo groups were explored. Low-dimensional representations of the taxonomic profiles computed using non-metric multidimensional scaling (MDS) on Bray–Curtis and Jaccard β-diversity scores suggested that there were no differences between the groups at any visit. These exploratory results were also confirmed with MiRKAT overall association tests based on β-diversity (Results shown in Finally, no difference between groups was observed regarding Changes at week 24 and 48 in the profile of total and individual SCFA were not significantly different between groups (
PMC10304064
4. Discussion
bone loss, osteopenia, fracture, osteoporosis
OSTEOPOROTIC FRACTURE, BONE LOSS, OSTEOPENIA, SECONDARY, OSTEOPOROSIS
To the best of our knowledge, this is the first randomized controlled trial (RCT) conducted to examine the effect of a hop extract on bone health in postmenopausal women with osteopenia. In this population, we demonstrated that a daily supplementation with 100 µg of 8-PN from a standardized hop extract for 48 weeks increased total body BMD compared to placebo. An improvement of the SF-36 physical functioning score was also observed in the HE group suggesting a higher perceived ability to perform daily activities. However, no significant effect was found in BMD at specific sites (lumbar spine, femoral neck, and total hip), plasma bone biomarkers, and other secondary outcomes, notably blood lipids and glucose homeostasis parameters.This beneficial impact on BMD is consistent with previous studies performed in the ovariectomized rat with standardized hop extract, which showed an increase in BMD following 8 to 12 weeks of supplementation while using a daily dose of 8-PN from 6 to 27 times higher in a human dose equivalent [Bone turnover biochemical markers help clinicians to identify patients at high risk for fracture and to monitor the efficacy of osteoporosis treatments. However, no significant difference between the HE and placebo groups was observed regarding the bone biochemical markers concentrations after 48 weeks of supplementation. Among the available biochemical markers, pro-collagen type I The magnitude of HE effects on bone density is not comparable to those of osteoporosis medications, but it could be of interest as a preventive measure for women with low bone mass that cannot be prescribed medication at this stage. Dawson-Hughes et al. have reported that after 3 years of vitamin D (700 IU) and calcium (500 mg) supplementation, a 1.1% net increase in total body BMD compared to placebo was associated with a relative risk reduction of 0.4 of first osteoporotic fracture in men and women [Dawnson Hugues et al. have reported in older women without intervention an annual bone loss of about 1% in the total body and 0.8% in the lumbar spine region [The main mechanism of action of HE is the estrogenic activity of 8-PN, which has been demonstrated in vitro and in vivo and which has been recently extensively reviewed [Despite the fact that volunteers were asked to maintain a similar diet throughout the study, significantly higher changes from baseline at week 48 were observed for fat, vitamin KAnother hypothesis for the important variability in response observed in this trial could be the inter-individual variation in prenylflavonoids metabolism that was reported previously [A novel aspect of this trial was the analysis of the participants’ gut microbiome and its relationship to the responsiveness of treatment. No difference between HE and placebo was observed for overall association parameters, alpha-diversity indices, and SCFA levels throughout the study, hence indicating no major shift in the gut microbiome composition and function. However, the explorative multivariate analysis indicated that after 48 weeks among the taxa identified as the most relevant to discriminate the two groups, there was notably a higher abundance of the genera Strengths of this study include the sample size calculation, the robust design (randomized, placebo-controlled, double-blind), the good adherence rate, the low drop-out rate, and the integrated analysis, including the impact of treatment on the microbiome and HE metabolites. The main limitation is the relatively short duration considering bone loss, as a duration of at least 2 years would incorporate more complete bone remodeling cycles and further strengthen the evidence provided by DXA in this trial. However, the bone remodelling cycle is known to last 120–200 days [To conclude, in postmenopausal women with osteopenia, daily consumption of a standardized hop extract with 100 µg of 8-PN during 48 weeks was found to have a beneficial increase of 1% of the total body BMD compared to placebo, above and beyond an increase associated with a calcium and vitamin D supplementation. Furthermore, even if no major shift of the gut microbiota composition was observed, modulation of some taxa previously identified as associated with bone loss was noted in the HE group and deserves further investigation. New clinical trials with notably a longer duration are needed to confirm the beneficial effect of standardized hop extract on bone health.
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Supplementary Materials
The following supporting information can be downloaded at: Click here for additional data file.
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Author Contributions
Conceptualization, M.L. and P.F.-B.; Formal analysis, D.T.; Investigation, M.T., T.B. and S.H.; Methodology, M.L.; D.T., M.T., T.B. and P.F.-B.; Writing—original draft preparation, M.L., D.T., R.R., T.B. and P.F.-B.; Writing—review and editing, M.L., D.T., R.R., M.T., T.B., S.H. and P.F.-B. All authors have read and agreed to the published version of the manuscript.
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Institutional Review Board Statement
MAY
The study was conducted in accordance with the Declaration of Helsinki and approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals (on 9 May 2019; Reference number ECM4(e) 07/05/19).
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Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
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Data Availability Statement
The data presented in this study are available on request from the corresponding author.
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Conflicts of Interest
M.L., M.T., T.B. and P.F.-B. are employees of Givaudan France Naturals. D.T. is an employee of Biofortis and was supported though a service agreement with Givaudan France Naturals. R.R has received fees for lectures or scientific advisory boards from Abiogen, Givaudan, Nestlé, ObsEva, and Theramex. S.H. reports no conflict of interest. The funders had no role in study conduct, analytical, and statistical analysis.
PMC10304064
Methods
bleeding, catheter occlusion, blood coagulation, catheter-related bloodstream infection, CRBSI
GASTROINTESTINAL BLEEDING, BLEEDING, SUBCUTANEOUS HEMATOMA
Using heparin saline and 4% sodium citrate as locking solution, then 152 patients in ICU undergoing infusion with central venous catheters, were randomly assigned to receive either 10 U/mL heparin saline or 4% sodium citrate. The used outcome indicators include: four indexes of blood coagulation at 10 minutes after locking and 7 d after the first locking, bleeding around the puncture site and subcutaneous hematoma rate, gastrointestinal bleeding rate, catheter indwelling time, catheter occlusion rate, catheter-related bloodstream infection (CRBSI) rate, rate of ionized calcium < 1.0 mmol/L. The main outcome indicator was the activated partial thromboplastin time (APTT) at 10 min after tube locking. The trial was approved by relevant authorities (Chinese Clinical Trial Registry, no: ChiCTR2200056615, registered on February 9, 2022,
PMC10317237
Results
Among the main outcome measures, the heparin group showed a significant increase in APTT compared to the sodium citrate group at 10 min after locking (LSMD = 8.15, 95%Cl 7.1 to 9.2,
PMC10317237
Conclusions
bleeding, catheter occlusion
BLEEDING, HYPOCALCEMIA
In ICU patients using CVCs (excluding dialysis catheters) infusion, employing 4% sodium citrate as a locking liquid can reduce the risk of bleeding and catheter occlusion without any hypocalcemia.
PMC10317237
Data Availability
All relevant data are within the paper and its
PMC10317237
1. Introduction
bleeding, HIT
BLEEDING
Central venous catheters (CVCs) in adults are inserted in the subclavian, jugular, or femoral vein, with the catheter tip positioned within the superior or inferior vena cava [According to the Infusion Nurses Society, 0–10 U/mL heparin saline is recommended as CVC locking fluid for ICU patients [To reduce the risks of bleeding and HIT, normal saline (0.9% sodium chloride) is suggested to replace heparin as the locking fluid of CVCs [Sodium citrate tube locking liquid has local anticoagulant property and hence it has no effect on coagulation function [Currently, numerous studies have been conducted to compare the effects of sodium citrate locking solution and heparin locking solution on central venous catheter (CVC) locking in hemodialysis patients. These studies consistently indicate that sodium citrate, as a catheter locking fluid, exhibits superior effectiveness and safety compared to heparin [Therefore, we conducted a pragmatic randomized controlled trial in which ICU patients were enrolled to compare the efficacy of 10 U/mL heparin saline and 4% sodium citrate in CVCs (excluding dialysis catheters) catheter locking from two aspects of therapeutic efficacy and safety.
PMC10317237
2. Material and method
PMC10317237
2.1. Study design
This study is a prospective, three-blind, randomized, parallel grouping, standard control, single-center clinical trial conducted according to the reporting specifications of randomized controlled trials (CONSORT). The checklist can be seen in
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2.2. Study participants
coagulation abnormalities
The first patient is enrolled on 31st December 2021 and the last patient is enrolled on 24th July 2022. The last observation is collected on 31st July 2022. We state that our CT registration was later that the date of enrolling the first patient because of the delay caused by the COVID-19 pandemic. Our CT registration actually was first submitted before December 31st, 2021, but it was not approved until February 9th, 2022 due to the extended review time of the website during the pandemic. Despite the CT registration being late, the trial still was conducted according to the original trial plan. (Chinese Clinical Trial Registry, no: ChiCTR2200056615, For real-world research purposes, we relaxed the criteria and did not exclude patients on anticoagulants (Including patients treated with continuous renal replacement therapy and treated with enoxaparin). Patients aged 18 to 80 years who received CVCs infusion during their ICU stay were enrolled. We excluded women during pregnancy, perinatal or lactation, and patients with heparin or sodium citrate allergy or coagulation abnormalities. If patients withdraw their informed consent, are removed from the ICU, die, or have a catheter removed, the study is considered to be discontinued. The first placement of CVCs in each patient was recorded.
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2.3. Randomization
The experimental group and the control group are randomly divided into 1:1. Random method: Random numbers are generated using SPSS 25.0 statistical software by the center’s personnel in charge of randomization, and group by the rank of the random number and group principle. Opaque envelopes are used to lock the results, and the envelopes are numbered. When a patient needs CVCs, the envelope is opened in numerical order to determine whether the patient is admitted to the experimental or control group. The allocation order is hidden until the end of the trial.
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2.4. Masking
bleeding, catheter occlusion
BLEEDING, SUBCUTANEOUS HEMATOMA
In this study, 2 nurses in the venous configuration center are responsible for marking test numbers and preparing locking fluids. No further cover-up is required because both types of locking fluids are colorless and odorless. The prepared locking solution is distributed to highly skilled and experienced ICU nurses who specialize in critical care. These nurses undertake the responsibility of performing the catheter locking procedure with utmost proficiency and expertise. Two additional investigators are tasked with the rigorous observation and systematic collection of clinical data. It is imperative that both investigators independently confirm the positive results (catheter occlusion, bleeding around the puncture site and subcutaneous hematoma) to ensure their validity and reliability. During the study, only the 2 nurses who prepare the tube-locking solution knew about the grouping situation, while the subjects, operators, investigators, and statisticians are all unaware of the grouping situations (
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2.5. Interventions
To ensure the reliability and authenticity of the experiments and reduce the bias caused by external factors, centralized training is conducted for the general nurses in the intensive care unit who participate in the research to achieve the purpose of homogenization.Selection of locking fluid and locking method: The selected subjects are all indwelled double-lumen catheters with single-use CVCs kit TYPE I (Henan Tuoren Medical Instrument Group Co., LTD.); specifications: 2-7FR-20cm, outer diameter of catheter 2.4 mm, length of catheter 20 cm. All catheters are inserted under ultrasound guidance and standard hygiene precautions are taken to minimize contamination.Experimental group: Taking 5 mL from a dose of 200 mL of 4% sodium citrate (Chengdu Qingshan Likang Pharmaceutical Co., LTD., Production batch NO. A2101013) as tube locking liquid.Control group: Taking 0.4 mL from a dose of 12500 u/2mL Heparin sodium injection (Chengdu Haitong Pharmaceutical Co., LTD., Approval no. H51021209) and adding 250 mL 0.9% sodium chloride injection as a mixture. After uniform preparation, a 5 mL mixture is taken as the tube locking liquid. The concentration of heparin in tube locking fluid is 10 U/mL.Flushing CVCs must be performed using turbulence with 10 mL 0.9% sodium chloride injection before and after each infusion, medication, parenteral nutrition, transfusion of blood products, and replacement of pipeline equipment. Sodium citrate tube locking solution is used in the experimental group, heparin tube locking solution is used in the control group and a positive-pressure locking technique is used to lock the tube. CVCs that are not currently in use are flushed and locked once a day [
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2.6. Outcome measure
bleeding, Catheter occlusion, catheter occlusion, pain, blood coagulation
GASTROINTESTINAL BLEEDING, BLEEDING, SUBCUTANEOUS HEMATOMA
Main outcome indicator: activated partial thromboplastin time (APTT) at 10 min after tube locking. Secondary outcome indicators: APTT at 7 d after initial tube locking, prothrombin time (PT) at 10 min after tube locking and 7 d after first tube locking, international normalized ratio (INR), fibrinogen (FIB), thrombin time (TT), catheter indwelling time, catheter occlusion rate, and CRBSI rate. Safety evaluation index: bleeding around the puncture site and subcutaneous hematoma rate, gastrointestinal bleeding rate, rate of ionized calcium < 1.0 mmol/L.Judgment criteria are as follows. Four indexes of blood coagulation include the blood of patients was drawn by venipuncture of peripheral blood before tube locking, 10 minutes after tube locking, and 7 d after the first tube locking, respectively, then comparing APTT, PT, INR, FIB, and TT. Catheter occlusion standard: (i) Partial occlusion. Infusion can be performed but blood cannot be withdrawn, the infusion rate is slowed down, local pain is present, there is resistance to flushing, or exudation occurs. (ii) Complete occlusion. It cannot be infused, withdrawn blood, or is unable to flush. When any of the above occurs, it is indicated by catheter occlusion [
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2.7. Statistical analysis
blood coagulation
Continuous variables are tested by histogram and Shapiro-Wilk test, and those that conformed to normal distribution are expressed as mean and standard deviation (SD); those that did not conform to normal distribution are expressed as median and quartile spacing. By performing covariance adjustment on the four indexes of blood coagulation prior to locking, the least-squares mean difference (LSMD) and its corresponding 95% confidence interval (95%CI) were computed. When the proportion of missing values was below 20% and the assumption of random missingness was made, multiple imputation by chained equations (MICE) was utilized to handle the missing variables. Specifically, predictive mean matching was employed to impute the missing values of the four indexes of blood coagulation 7 d after the initial locking [Due to the uneven distribution of the catheter insertion location as baseline data, we performed a post hoc analysis to adjust this confounding factor: using the internal jugular vein and subclavian vein as subgroups, an analysis of covariance is performed in the four indexes of blood coagulation 10 minutes after locking, and a forest map is drawn. The α segmentation is used to control class I errors that come from multiple comparisons, and To get the following data, before the start of the experiment, a two-month pre-experiment is conducted. The results show that the mean APTT of the control group is 36.74±4.74 seconds, and the mean APTT of the experimental group is 32.84±7 seconds. Setting two-sided α = 0.05 and the power is 90%, the sample size of the experimental group N1 = 51 cases and the sample size of the control group N2 = 51 cases are calculated by PASS 15 software. Taking into account the 20% loss to follow-up and refusal to follow-up, at least 64 subjects in the experimental group and 64 subjects in the control group are finally required, and a total of at least 128 cases are included. This study includes 152 subjects totally. Sample size calculation was only conducted for the main outcome indicator, namely the APTT at 10 min after tube locking. The lack of sample size calculation for the remaining outcome measures may have led to inadequate statistical power and an increased risk of type II error, thereby potentially yielding false-negative results.All data are analyzed using the IBM SPSS Statistics for Windows (SPSS, ver. 25.0, USA) and R software (version 4.2.1, available at
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2.8. Ethics approval and consent to participate
MAY
This study has been reviewed and approved by the medical ethics committee and the academic committee of Zhongjiang County People’s Hospital (ethics approval number: JLS-2021-034, date of approval May 10, 2021; JLS-2022-027, date of approval May 30, 2022; medical research record number: MR-51-21-014013). Since the patient is in a critical condition and has no ability to sign the consent form, the patient’s close relatives (parents, children, siblings) act as agents to sign the informed consent form. The ethics committee was aware of and approved this consent procedure. The trial was conducted in agreement with the updated Declaration of Helsinki.
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3. Results
PMC10317237
3.1. Patient population
Out of the 152 patients, 148 are randomized and completed the trial. On an intention-to-treat (ITT) principle, 78 patients are assigned to the 4% sodium citrate group and 70 patients to the heparin group (
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CONSORT flowchart.
Baseline characteristics between the two groups are similar except for the catheter insertion location and APTT before locking (
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3.2. Primary endpoint
After adjusting for the APTT index prior to tube locking, the APTT levels were found to increase significantly in the heparin group compared to the sodium citrate group at 10 minutes after locking (LSMD = 8.15, 95%CI 7.1 to 9.2,
PMC10317237
APTT 10min after locking.
After adjusting for the APTT index prior to tube locking, the APTT levels were found to increase significantly in the heparin group compared to the sodium citrate group at 10 minutes after locking (LSMD = 8.15, 95%CI 7.1 to 9.2, Due to the uneven distribution of catheter insertion location, a post hoc analysis is performed using the internal jugular vein and subclavian vein as subgroups. In the internal jugular vein group, there was a significant increase in APTT levels in the heparin group compared to the sodium citrate group at 10 minutes after tube locking (LSMD = 8.55, 95%CI 6.13 to 10.97,
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Forest map of four indexes of blood coagulation 10 minutes after locking.
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3.3. Secondary endpoints
blood coagulation
Among the four indexes of blood coagulation at 10 min after tube locking, after adjusting the PT index before tube locking, the heparin group increases compared with the sodium citrate group (LSMD = 0.86, 95%CI 0.12 to 1.61, Since the four indexes of blood coagulation are missing 7 d after the tube locking, the MICE method is used to fill in them. Compared with the sodium citrate group, the APTT (LSMD = 8.05, 95%CI 6.71 to 9.4,
PMC10317237
Four indexes of blood coagulation 7 d after the first locking.
blood coagulation
Through the implementation of analysis of covariance to adjust for the four indexes of blood coagulation prior to locking, the least-squares mean difference was employed to describe the observed outcomes. Furthermore, multivariate imputation using chained equations (MICE) methodology was applied to address missing data and ensure comprehensive data completion.APTT activated partial thromboplastin time, PT prothrombin time, INR international normalized ratio, FIB fibrinogen, TT thrombin time95%CI, 95% confidence intervalThere are 627 catheter days in the heparin group and 674 catheter days in the sodium citrate group. The median catheter indwelling time between the two groups is 7 d, and the difference is not statistically significant (
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3.4. Safety evaluation index
bleeding
BLEEDING, SUBCUTANEOUS HEMATOMA
There are 9 cases (12.9%) of bleeding around the puncture site and subcutaneous hematoma in the heparin group, and 1 case (1.3%) in the sodium citrate group, and the difference is statistically significant (RR = 0.1, 95%CI 0.01 to 0.77,
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4. Discussion
coma, perioral numbness, catheter occlusion, blood coagulation
BACTERIAL RESISTANCE, COMA
A pioneering pragmatic randomized controlled trial has been designed to compare the effects of 10 U/mL heparin saline and 4% sodium citrate as locking solutions for CVCs (excluding dialysis catheters).After using heparin to lock the tube, it will affect the four indexes of blood coagulation, resulting in elevated APTT (LSMD = 0.86, 95%CI 0.12 to 1.61, In patients infused with CVCs, catheter occlusion rate using heparin-locking solutions has been estimated in the range of 0% to 33% [Theoretically, the use of sodium citrate as a tube locking solution can reduce the CRBSI rate because metal ions play a key role in stabilizing the extracellular matrix of microbial biofilms, in which sodium citrate exhibits antibacterial activity by depriving microorganisms of these essential metal ions without worrying about bacterial resistance [Regarding safety, because most of our patients are in a state of sedation and analgesia or coma, it is impossible to ask the patients about their perioral numbness. Fortunately, ionized calcium is monitored, finding that the rate of ionized calcium < 1.0 mmol/L in the heparin group and the sodium citrate group is similar (We have to acknowledge some limitations to our study. The study is conducted in a tertiary hospital with a dedicated team of physicians and an intravenous access support team, factors that may have positively affected the results. Due to the simple randomization method used in our study, the two baseline data, APTT and catheter insertion location, are inevitably distributed unevenly, so we used some statistical methods to adjust these confounding factors, such as ex ante analysis of covariance and post hoc subgroup analysis. We had 21 patients (14.2%) who withdrew from the study within the 7-day observation period (transferred from the ICU, died, or had the catheter pulled out), so the data for the four indexes of blood coagulation 7 d after the locking of the catheter contained missing values. The missing data are 9 cases (12.9%) in the heparin group and 12 cases (15.4%) in the sodium citrate group, respectively. We filled in the missing data and performed a sensitivity analysis to evaluate the robustness of the results. The sample size calculation is only performed for main outcome indicator, and the absence of sample size calculation for other outcome measures may have compromised statistical power and increased the risk of type II error, potentially resulting in false-negative findings. There are also some regrets that we did not collect whether blood products and parenteral nutrition are infused, which are risk factors for catheter occlusion. A data safety monitoring board is not used in this study since no interim analyses were undertaken.
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5. Conclusions
bleeding, catheter occlusion
BLEEDING, HYPOCALCEMIA
In this prospective, triple-blind, randomized, parallel-group, standard-controlled, single-center trial, the efficacy and safety of 4% sodium citrate are demonstrated as a tube locking solution. In ICU patients receiving CVCs infusion, the use of 4% sodium citrate to lock the catheter can reduce the risk of bleeding and catheter occlusion without the occurrence of hypocalcemia.Our work show that the 4% sodium citrate is possible to replace heparin as a tube-locking solution for CVCs (excluding dialysis catheters). Hence, we propose that additional prospective studies be done, which (i) use the same primary outcome, (ii) allow broader inclusion criteria, and (iii) involve multiple centres.
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Supporting information
PMC10317237
Four indexes of blood coagulation 10 minutes after locking.
(DOCX)Click here for additional data file.
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Four indexes of blood coagulation 7 days after the first locking.
(DOCX)Click here for additional data file.
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CONSORT 2010 checklist of information to include when reporting a randomised trial.
(DOC)Click here for additional data file.
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Team composition and overall research procedures.
(DOCX)Click here for additional data file.
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Flushing and locking procedures.
(DOCX)Click here for additional data file.(DOCX)Click here for additional data file.(DOCX)Click here for additional data file.We would like to express our gratitude to the strong support of the nursing team in the Department of Critical Care Medicine of People’s Hospital of Zhongjiang County, who flushed and locked the catheter. Thanks to Ying Liu and Xiaorong Yang for data collection, arrangement and input. We also thank all patients and their families for their participation.
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Abbreviations
Central venous cathetersIntensive
Central venous cathetersIntensive care unitCatheter-related bloodstream infectionHeparin-induced thrombocytopeniaActivated partial thromboplastin timeProthrombin timeInternational normalized ratioFibrinogenThrombin timeRelative riskLeast-squares mean difference
PMC10317237
References
PMC10317237
1. Introduction
malnutrition, NSDs
MALNUTRITION
The purpose of this study was to compare the effects of nutritional supplement drinks (NSDs) and nutritional education (NE) on the nutritional status and physical performance of older nursing home residents who were at risk of malnutrition. This study was a clustered, randomized, parallel, multi-center clinical trial, with 107 participants more than 65 years old and at risk of malnutrition recruited from several nursing homes in this study. Participants were divided into two groups: an NE group (The World Health Organization (WHO) estimates the total number of older or older people (≥60 years) worldwide will surpass 1.2 billion by 2025 [The WHO reported that the prevalence of malnutrition in older people ranges from 1.3% to 47.8% [Oral nutritional supplements (ONSs) can provide high-quality nutrients and are easy to prepare, and they are an ideal choice to provide protein and energy in patients and older individuals [Several studies demonstrated the unique effects of ONSs in improving the nutritional status of older adults, but most studies focused on the late stage of malnutrition [
PMC10574690
2. Materials and Methods
PMC10574690
2.1. Study Design
dysphagia, NSD
DYSPHAGIA
This study was a clustered, randomized, parallel, multicenter clinical trial that was approved by the Taipei Medical University (TMU)-Joint Institutional Review Board (ID: N202011065, 27 January 2021) and ClinicalTrials.gov Protocol Registration and Results System (NCT04857463, 20 April 2021).Participants who met the criteria were divided into two groups: an NE (NE) group and an NSD group. The experimental period was 12 weeks. Participants in the NE group received NE offered by a dietitian, twice in the first 6 weeks and once in the last 6 weeks. For the NE, the Geriatric Nutrition Handbook from the Taiwan Health Promotion Administration was used, which includes daily dietary guidelines and how to eat when dysphagia and gastrointestinal discomfort occur. Except for regular nutritional education in the NE group, the NSD group was provided with two packs of NSD (Mei Balance, Meiji Holdings, Tokyo, Japan) per day as a snack between meals and before bed. The nutrient contents of the NSD are shown in
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2.2. Participant Recruitment
chronic kidney disease, Malnutrition, cancer, NSD, Hypertension, weight loss, diabetes
HYPERLIPIDEMIA, MALNUTRITION, CANCER, RECRUITMENT, CHRONIC DISEASES, ACUTE DISEASE, HYPERTENSION, MALNUTRITION, DIABETES
Regarding inclusion criteria, participants who were older than 65 years and had the Malnutrition Universal Screening Tool (MUST) score of ≥1 were considered at risk of malnutrition. The MUST score was evaluated by three factors such as BMI, unplanned weight loss, and acute disease effects. Additionally, participants were not allowed to accept any ONSs at the time of recruitment for this study. The exclusion criteria included subjects who have chronic diseases, such as diabetes undergoing insulin therapy, chronic kidney disease, and cancer. Hypertension and hyperlipidemia, without taking medicine, were not excluded in this study.There were four nursing homes in this study, including (1) Taipei Veterans Home, Veterans Affairs Council, (2) Ren-ai Senior Citizens Home, New Taipei City Government, (3) Northern Region Senior Citizens’ Home, Ministry of the Interior, and (4) Hygge Healthcare. The group assignment was determined through a random selection process, where participants within the same nursing home were assigned to the same group. This was carried out to avoid participants comparing whether they received oral nutritional supplements with each other. As a result, (1) and (2) were NE groups, while (3) and (4) were NSD groups. Regarding the recruitment process, the staff members of the project took the opportunity to explain the details of the experiment to the participants during the group activities. This included providing information about the purpose of the study, the intervention being tested, and the potential benefits and risks. Staff members also emphasized the voluntary nature of participation and assured them of their right to withdraw from the study at any time without consequences. After the explanation, those participants who expressed a willingness to participate were asked to remain for further assessment, such as the MSUT score and medical history. Participants who achieved inclusion/exclusion criteria were then given the opportunity to discuss their participation with their family members. Finally, participants who expressed continued willingness to participate after discussing with their family members were asked to sign a consent form. This formalized their agreement to be part of the experiment and marked their official entry into the study.
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2.3. Anthropometric Data
muscle mass, appendicular skeletal muscle mass
ASMI
Anthropometric measurements were conducted using Karada scan 371 (Omron Kabushiki-Gaisha, Kyoto, Japan) including BW, percentage of muscle mass, and percentage of body fat. The appendicular skeletal muscle mass index (ASMI) was calculated based on the BW, percentage of muscle mass, and height. The calculation formula was BW (kg) × muscle mass (%) ÷ height
PMC10574690
2.4. Blood Pressure
BLOOD
Blood pressure data, including systolic (SBP) and diastolic blood pressure (DBP), were collected by daily records of the nursing home and were measured with an Omron HBP-9020 (Omron Corporation, Tokyo, Japan).
PMC10574690
2.5. Physical Performance
OSTEOPOROTIC FRACTURES
The Study of Osteoporotic Fractures (SOF) index was used to assess the frailty of older participants [
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2.6. Dietary Calorie Intake and Nutritional Status
malnutrition
MALNUTRITION
The daily calorie intake and the Mini-Nutritional Assessment Short Form (MNA-SF) were assessed by a dietitian. Regarding the dietary intake, since the nursing home provided the same meals to all residents; the calorie intake was estimated based on the remaining portion of each participant’s meal. The MNA-SF was used to assess the nutritional status, with scores of 12~14 considered no risk of malnutrition, 8~11 considered at risk of malnutrition, and 0~7 considered malnutrition [
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2.7. Blood Biochemical Analyses
Fasting blood samples were analyzed with the ADVIA 1800
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2.8. QOL and Health Status
MOS
The physical and mental components scale of the MOS 36-Item Short Form Health Survey (SF-36) were used to monitor QOL and the health status [
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2.9. Statistical Analysis
All values are expressed as the mean and standard deviation (SD) or
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3. Results
PMC10574690
3.1. Basic Information
A study flow diagram is shown in
PMC10574690
3.2. Baseline Demographics, Anthropometric Assessments, and Dietary Intake of Study Participants
As shown in
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3.3. Body Composition, Physical Performance, and Nutritional Status
PMC10574690
3.3.1. Changes after the NSD Intervention
NSD
In the NSD group, compared to the baseline, BW and BMI had significantly increased after 12 weeks of the NSD intervention. The SOF score had significantly decreased while walking speed had significantly increased at the endpoint compared to the baseline. Moreover, the MNA-SF score was significantly higher at the endpoint compared to the baseline (
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3.3.2. Changes after the NE Intervention
In the NE group, there were no differences in any parameters after 12 weeks of NE (
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3.4. Blood Biochemical Analysis
BLOOD
Blood biochemical parameters are shown in
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3.5. Vit. D and Zinc Deficiencies
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3.5.1. Changes after the NSD Intervention
In the NSD group, 42.1% of participants exhibited a Vit. D deficiency and 31.6% of participants had an insufficient level at the baseline (
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3.5.2. Changes after the NE Intervention
NA DEFICIENCY
In the NE group, 42.0% of participants had a deficiency and 42.0% of participants had an insufficient level of Vit. D at the baseline (
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3.5.3. Comparison of the Vit. D and Zinc Statuses between the NSD and NE Groups
The NE group had more participants with sufficient zinc at the baseline compared to the NSD group. However, there were no differences in percentages of participants with deficiencies in the Vit D and zinc statuses at the end of the study between the two groups (
PMC10574690