Clinical Nutrition 43 (2024) 124e133
Contents lists available at ScienceDirect
Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu
Meta-analyses
Glutamine enteral therapy for critically ill adult patients: An updated
meta-analysis of randomized controlled trials and trial sequential
analysis
Baofang Liang a, 1, Jianwei Su c, 1, Jie Chen d, Hanquan Shao d, Lihan Shen d, **,
Baocheng Xie b, *
a
Department of Healthcare-associated Infection Management, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital),
Dongguan, Guangdong, China
b
Department of Pharmacy, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong, China
c
Department of Clinical Pharmacy, Dongguan Tungwah Hospital, Dongguan, Guangdong, China
d
Department of Critical Care Medicine, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan, Guangdong,
China
a r t i c l e i n f o
s u m m a r y
Article history:
Received 21 September 2023
Accepted 12 November 2023
Background: The efficacy of supplemental enteral glutamine (GLN) in critical illness patients remains
uncertainty.
Objective: Based on a recently published large-scale randomized controlled trials (RCTs) as regards the
use of enteral GLN, we updated a meta-analysis of RCTs for further investigating the effects of enteral
GLN administration in critically ill patients.
Methods: We searched RCTs reporting the impact of supplemental enteral GLN about clinical outcomes
in adult critical illness patients from EMBASE, PubMed, Clinical Trials.gov, Scopus and Web of Science and
subsequently registered the protocol in the PROSPERO (CRD42023399770). RCTs of combined enteralparenteral GLN or parenteral GLN only were excluded. Hospital mortality was designated as the primary outcome. We conducted subgroup analyses of primary outcome based on specific patient populations, dosages and therapy regimens, and further performed trial sequential analysis (TSA) for clinical
outcomes.
Results: Eighteen RCTs involving 2552 adult critically ill patients were identified. There were no
remarkable influences on hospital mortality regardless of different subgroups (OR, 1.05; 95% CI, 0.85
e1.30; p ¼ 0.67), intensive care unit (ICU) length of stay (LOS) (MD, 0.07; 95% CI, 1.12 e 0.98; p ¼ 0.89)
and infectious complications (OR, 0.90; 95% CI, 0.75e1.10; p ¼ 0.31) with enteral GLN supplementation.
Additionally, the results of hospital mortality were confirmed by TSA. However, enteral GLN therapy was
related to a reduction of hospital LOS (MD, 2.85; 95% CI, 5.27 to 0.43; p ¼ 0.02).
Conclusions: In this meta-analysis, it seems that enteral GLN supplementation is unlikely ameliorate
clinical outcomes in critical illness patients except for the reduction of hospital LOS. Our data do not
support enteral GLN supplementation used routinely in critical illness patients.
© 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Keywords:
Glutamine
Enteral
Critically ill
Randomized controlled trials
Mortality
Meta-analysis
Abbreviations: GLN, Glutamine; RCTs, Randomized controlled trials; TSA, Trial sequential analysis; ICU, Intensive care unit; LOS, Lengths of stay; ASPEN, American Society
for Parenteral and Enteral Nutrition; ESPEN, European Society for Parenteral and Enteral Nutrition; PRISMA, Preferred Reporting Items for Meta-Analyses; MH, MantelHaenszel; OR, Odds ratio; MD, Mean difference; CIs, Confidence intervals; IQRs, Interquartile ranges; SD, Standard deviation.
* Corresponding author.
** Corresponding author. Department of Pharmacy, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), No.78 Wan-Dao Road, WanJiang District 523059, Dongguan, Guangdong, China.
E-mail addresses: shenlihan@hotmail.com (L. Shen), baochengxie@smu.edu.cn (B. Xie).
1
Baofang Liang and Jianwei Su contributed equally to this work.
https://doi.org/10.1016/j.clnu.2023.11.011
0261-5614/© 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
B. Liang, J. Su, J. Chen et al.
Clinical Nutrition 43 (2024) 124e133
1. Introduction
2.2. Study selection and data extraction
Critical illness patients often expose to catabolic stress that can
result in malnutrition. Hence, most critically ill patients require
nutritional supports, with enteral nutrition more beneficial than
intravenously [1]. Glutamine (GLN), an immune nutrient, is related
to the normal function of the intestinal tract and immunologic
system. Plasma GLN levels fall significantly during critical illness,
and this drop may be associated with the decreased host resistance
to infection [2], and may lead to poor outcomes [3,4] including
increased probability of infection risk, or worse, increased mortality rate [5]. As a consequence, enteral GLN therapy is considered
to be beneficial to the clinical outcomes of patients with critically
ill, as well as causes particular increasing interest [6].
The effect of supplemental enteral GLN in patients with critically ill remains uncertainty. Some animal studies provided evidence for benefits from GLN supplementation with reduction of
bacterial translocation [7] and survival improvement [8,9]. Previous RCTs have demonstrated that enteral GLN supplementation
may decrease infection rates [10e12], the hospital length of stay
(LOS) [12e15] and hospital mortality rates [11] in critical illness
patients. Whereas, these studies were small trials with poor
quality. Recently, some meta-analyses [16,17] and RCTs [18e20]
reported that supplemental enteral GLN does not ameliorate
significantly in critically ill patients. According to weak evidence,
major nutrition guidelines provide discordant recommendations
for supplemental enteral GLN to critical illness patients. The
American Society for Parenteral and Enteral Nutrition (ASPEN)
suggests that supplemental enteral GLN should not be administrated to regular enteral nutrition in critical illness patients [21].
Nevertheless, European Society for Parenteral and Enteral Nutrition (ESPEN) recommends additional enteral GLN should be
administered to intensive care unit (ICU) patients with burn or
trauma [22], which suggests that different population groups may
benefit differently. At present, few systematic analyses concentrated on enteral GLN therapy for severe illness has been performed. In consideration of the inconsistency in the available
literature and the recent publication of the latest large-scale RCT
involving new evidence on this subject [18], it is required to update the meta-analysis included RCTs to re-assess the role of
enteral GLN therapy, which may estimate the impact of GLN in
critically ill patients more precisely and accurately.
Our aim of this meta-analysis is to assess the efficacy of GLN
enteral therapy in critically ill patients, and further explore the
effects of patient populations, dosages and treatment regimens
subgroup on primary clinical outcome. Trial sequential analysis
(TSA) is applied to validate the robust and conclusive of currently
evidence.
We searched databases including EMBASE, PubMed, Clinical
Trials.gov, Scopus and Web of Science from inception to October
23, 2023 to obtain RCTs with subject terms and uncontrolled
terms. The last search was on October 23, 2023. The detail of
search strategy was presented in supplemental data
(Supplemental Table S1). We hand-searched the relative references of review literature as well. Two authors evaluated the titles
or abstracts independently to analyze whether they met the inclusion and exclusion criteria by using NoteExpress software. Any
disagreements during literature research or data collection were
solved by consensus in the following discussion with a third party
author.
For each included study, the information were extracted using
excel form by two reviewers independently. The following parameters were collected: study characteristics, baseline characteristics, interventions, patient populations, clinical outcomes and so
on.
2.3. Risk of bias assessment
The methodological quality of enrolled RCTs was assessed by
two authors independently using the Cochrane risk of bias tool to
determine the bias risk [24]. The Cochrane risk of bias are summarized as follows: randomization process, allocation concealment, blinding of participants, personnel and outcome data,
incomplete outcome, selection of reported result and other bias. If
there were any difference in opinion, a third reviewer was asked to
participate in consultation.
2.4. Statistical analysis
Based on heterogeneity, Review Manager 5.5 was applied to
included trials by the Mantel-Haenszel (MH) or inverse variance
method using random effect or fixed effect models for dichotomized and continuous data respectively. We combined data from
RCTs to calculate the pooled odds ratio (OR) for dichotomized data
and mean difference (MD) for continuous data with 95% confidence intervals (CIs). If standard deviation (SD) was not reported,
available medians and interquartile ranges (IQRs) were converted
to SD. To evaluate heterogeneity across the trials, we tested the
potential statistical heterogeneity by a weighted MH chi-square
test or the I2 test as implemented in Review Manager 5.5. Any
substantial heterogeneity was predefined as p value of chi-square
test <0.05 or I2 > 50%. We used fixed effect model in the metaanalysis unless obvious heterogeneity existed in trials. Reasons
for heterogeneity were explored through undertaking sensitivity
analyses. To evaluate publication bias quantitatively, we carried
out funnel plots as well as Egger's test for primary outcome. If
primary outcome with publication bias, stability was detected by
trim and fill analysis. Meanwhile, trials with unknown or high bias
risk was further explored through sensitivity analysis. Review
Manager 5.5 and STATA software V12 were applied to perform
statistical analyses. p < 0.05 was deemed to be statistically
significant.
2. Methods
This study conducted according to the Preferred Reporting Items
for Meta-Analyses (PRISMA) statement [23], and was subsequently
registered in the PROSPERO (CRD42023399770).
2.1. Study inclusion criteria
To increase statistical power, RCTs were chosen if they met the
below features: 1) Study design: RCT; 2) Study population: adult
patients with critically ill (18 years old) who were admitted to
ICU; 3) Intervention: enteral GLN supplementation compared with
control group, placebo or no intervention); 4) Study outcomes:
primary outcome: hospital mortality, if not described, 28/30-day or
ICU mortality was eligible; secondary outcomes: hospital and ICU
LOS and infection complications.
2.5. Subgroup analyses
For hospital mortality, subgroup analyses were undertook to
determine potential factors on the impact of enteral GLN therapy.
We investigated if there were various therapy effects of supplemental enteral GLN in specific patient populations (burn, trauma
or mix ICU patients), dosages (< 0.3 g/kg/d, 0.3 e 0.5 g/kg/
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Clinical Nutrition 43 (2024) 124e133
d or > 0.5 g/kg/d) and therapy regimens (monotherapy or combined therapy).
3. Results
3.1. Study identification and selection
As shown in Fig. 1, according to our inclusion criteria, we
identified 4698 records from database and 839 overlapping
studies were removed before screening. 3821 records were
excluded referred to titles or abstracts. The remaining 28 records
were retrieved as qualified, of which ten were considered unqualified
and
excluded.
Finally,
18
eligible
RCTs
[10e15,18e20,27e35] enrolling 2552 ICU patients were included
in our study.
We totally included 18 trials that supplemented with enteral
GLN in critically ill patients [10e15,18e20,27e35]. Three trials were
conducted in multicenter [10,18,27] and fifteen were single center
[11e15,19,20,28e35]. Of these trials, five trials included critically ill
patients were burn patients and four were trauma patients. The
overall description reported in each trial involving study
2.6. Trial sequential analysis
Adding new RCTs to cumulative meta-analysis cloud cause type I
errors [25], which result in erroneous conclusions, even inappropriate
clinical practice. Trial sequential analysis (TSA) can control the risk of
random error and help to test the imprecision of the level of evidence
[26]. Cumulative Z curve crossing trial sequential monitoring
boundary or the futility area indicates the current interventions effect
have a high certainty, and no further trials are required to confirm the
efficacy. Whereas, evidence is insufficient to draw a conclusion when
cumulative Z curve neither enters any of the boundaries nor achieves
the required information size. When TSA program software was
applied to clinical outcomes, the type I error was 5% and type II error
was 20% (version 0.9.5.10 beta) (http://www.ctu.dk/tsa).
Fig. 1. PRISMA 2020 flow diagram for the meta-analysis.
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Clinical Nutrition 43 (2024) 124e133
3.4. Subgroup analyses
characteristic, population, setting, intervention, age and sex are
described in Supplemental Table S2.
We conducted a subgroup analysis in accordance with whether
the patients were burn, trauma or ICU to determine the impact on
hospital mortality in specific patient populations. No prominent
difference existed in hospital mortality of three subgroups
(Supplemental Fig. S1. A). TSA implementation overlooked the
boundary for requested information size in subgroups of burn and
trauma patients due to limited available information. Type II error
was observed in the subgroup of ICU patients (Supplemental Fig. S1.
B-D).
We also conducted a subgroup analysis according to enteral GLN
dosages (< 0.3 g/kg/d, 0.3 e 0.5 g/kg/d or > 0.5 g/kg/d). As presented in Supplemental Fig. S2. A-D, no obvious difference existed
in hospital mortality among all subgroups and TSA showed that
there is a lack of evidence to confirm the conclusion.
Finally, we evaluated a subgroup analysis according to whether
the patients were given enteral GLN monotherapy or combined
with other formulations such as antioxidant. Two subgroups
showed no remarkable difference in hospital mortality. By performing TSA, type II error was detected in the combined therapy
subgroup, while futility was found in monotherpy subgroup
(Supplemental Fig. S3. A-C).
3.2. Risk of bias and quality assessment
Figure 2 depicted each RCT on the seven domains. Two of these
RCTs got an overall rating of low risk of bias, five RCTs had a highrisk of bias due to blinding the participants and personnel, followed
by attrition bias (3 RCTs), reporting bias (3 RCTs) and selection bias
(1 RCT).
3.3. The impact on mortality
Aggregated data from 16 of the 18 identified trials
[10e13,15,18e20,27,28,30e35] enrolled a total of 2552 patients, no
obvious effect on hospital mortality with enteral GLN supplementation was observed, and the heterogeneity was not significantly
different (OR, 1.05; 95% CI, 0.85e1.30; p ¼ 0.67; I2 ¼ 0%) (Fig. 3A). As
shown in Fig. 3B, the cumulative Z curve did not reach the
requested information size, which was calculated to be 3994 patients for primary outcome, but entered the futility area. Thus, it
indicated that currently cumulative evidence is futility result, and
further trials will not be needed to confirm the conclusion.
Fig. 2. Risk of bias and quality assessment (A) Risk of bias summary. (B) Risk of bias.
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Clinical Nutrition 43 (2024) 124e133
Fig. 3. The effect of enteral GLN on hospital mortality; (A) Forest plot of hospital mortality; (B) TSA for hospital mortality.
cumulative Z curve neither entered the conventional boundary nor
crossed the trial sequential futility area, as well as that the
requested information size was not achieved, suggesting that
further trials will be needed to confirm the conclusion (Fig. 6B).
3.5. The impact on hospital LOS
As shown in Fig. 4A, we found that enteral GLN supplementation
was significantly reduced hospital LOS when fourteen studies were
aggregated in which reporting data on hospital LOS (MD, 2.85; 95%
CI, 5.27 to 0.43; p ¼ 0.02; I2 ¼ 64%) [11e15,18,20,27,28,
30e32,34,35]. Although the cumulative Z curve did not achieve the
requested information size, it both entered the traditional boundary
and the trial sequential monitoring boundary, indicating that it was
true positive result for hospital LOS (Fig. 4B).
3.8. Publication bias
For hospital mortality, publication bias was evaluated by funnel
plots, and asymmetry was observed when visually assessing.
Obvious publication bias was detected in the Egger's test
(p ¼ 0.038), however, trim and fill analysis revealed the result of
hospital mortality in this meta-analysis was robust. Additionally,
there was no publication bias (p ¼ 0.09) when an outlier trial was
eliminated [11]. Sensitivity analysis was further undertook to
identify the source of intertrial heterogeneity, which revealed that
no trial is the source of intertrial heterogeneity in hospital mortality
(Supplemental Figure S1. A-D).
3.6. The impact on ICU LOS
As shown in Fig. 5A, no obvious difference was observed on ICU
LOS when ten studies were aggregated in which reporting data on
ICU LOS (MD, 0.07; 95% CI, 1.12 e 0.98; p ¼ 0.89; I2 ¼ 7%)
[10,19,20,27e30,32e34]. However, boundary requested information size is ignored due to too little information use (0.28%) when
performing TSA (Fig. 5B).
4. Discussion
Our meta-analysis revealed that enteral GLN therapy in critical
illness patients is unconnected with prominent improvement in
hospital mortality and other relevant outcomes, with the exception
of hospital LOS. We did not detect heterogeneity or high signals of
publication bias effect with respect on hospital mortality, especially
after deleting outlier trial. Additionally, no significant differences
were observed on hospital mortality of different subgroup analyses
3.7. The impact on infection complications
To identify the impact of supplemental enteral GLN on the infectious complications, eleven studies included 2351 patients were
assessed [10e13,18,19,27,28,31e33]. As shown in Fig. 6A, no
remarkable effect was observed on the infection complications (OR,
0.90; 95% CI, 0.75e1.10; p ¼ 0.31; I2 ¼ 41%). By performing TSA, the
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Clinical Nutrition 43 (2024) 124e133
Fig. 4. The effect of enteral GLN on hospital LOS; (A) Forest plot of hospital LOS; (B) TSA for hospital LOS.
limited number of burn patients in single-center, and only one trial
by Garrel. et al. showed that the enteral GLN supplementation
cloud reduce mortality [11]. Single-center RCTs were inclined to
generate positive effects than multicenter RCTs [41]. After inclusion
of five RCTs with 1351 burn patients, of which one was a large-scale
international multicenter RCT, our results were aligned with the
latest meta-analysis reported that enteral GLN was not efficacious
in burn patients [42]. Moreover, similar to prior meta-analysis, no
benefit from supplemental enteral GLN on hospital mortality was
confirmed in severe trauma in our result. Consequently, the specific
ESPEN guideline should re-evaluate the role of enteral GLN supplementation, which recommends that additional enteral GLN
should be given in burn patients (burns >20% of body surface area)
and critical trauma patients [22].
It was reported that lower GLN concentrations have higher
mortality rate than those with normal GLN concentrations in critical illness patients [43]. Five RCTs examining the baseline GLN level
were included for subgroup analysis of mortality. Four RCTs reported mortality in patients with baseline GLN level below 420
umol/L [39], and one RCT with baseline GLN level of 420e930 mmol/
L. Patients either with a normal GLN level or below normal GLN
level cannot benefit from enteral GLN supplementation. Although
there is no heterogeneity, this result should be interpreted with
caution due to small sample size. The dosage of GLN administered
to critically ill patients is an important consideration, however, our
data failed to reveal a correlation between enteral GLN
including specific patient populations, dosages and therapy
regimens.
TSA supported that enteral GLN supplementation has no positive effect on hospital mortality, but has positive result on hospital
LOS. No further RCTs are needed to conduct for hospital mortality
and hospital LOS as more trials are less likely to change these
findings. On the other hand, result from TSA of infection complication was shown to be type II error with uncertainty.
Enteral nutrition is the optimized administration route for patient with critically ill as it preserves gut barrier function, reduces
infectious complications [36,37], and GLN appears to protect the
integrity of intestinal mucosa, thereby preventing increasing intestinal permeability and bacterial translocation [38]. Consistent
with prior meta-analyses [16,17,39,40], our results aggregating 18
RCTs with 2552 patients with critically ill revealed that there was
no prominent mortality benefit from enteral GLN supplementation
in critically ill patients. We further found that there was no statistical significance according to the results of predefined subgroup
analyses in different patient populations, dosages and therapy
regimens. In spite of a trophic effect of enteral GLN in sustain intestinal integrity, its inability to produce enough systemic antioxidant effects might clarify the deficiency of clinical outcomes benefit
partly [1]. Our subgroup result of burn patient was discordant with
meta-analysis of van Zanten AR et al. aggregated three RCTs with
115 burn patients [16], which considered that there may be a significant benefit from enteral GLN. However, these RCTs included
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Clinical Nutrition 43 (2024) 124e133
Fig. 5. The effect of enteral GLN on ICU LOS; (A) Forest plot of ICU LOS; (B) TSA for ICU LOS.
patients. The route of GLN administration may be an important
factor. Several studies provided low to moderate evidence that GLN
supplementation could diminish the rate of infectious complications in critically ill patients, but it was worth noting that no benefit
was observed on infectious complications in the subgroup analysis
of enteral administration route [39,40,46], indicating that the
beneficial effect may be mainly related to parenteral GLN supplementation. A possible reason for this result may be that enteral GLN
supplementation is not effectively absorbed as many ICU patients
are affected by gastrointestinal dysfunction [39].
Our meta-analysis has numerous strengths. This meta-analysis
included the latest large-scale international RCT in burn patients.
Furthermore, the TSA analyses allow us to assess the repetitive
testing risk, which added to the robustness of this meta-analysis. In
addition, RCTs involving nutritional intervention are very expensive
and logistically difficult. Our TSA demonstrated futility of enteral
GLN on mortality, and no further trials will need to perform. These
features reduced bias and improved the accuracy of our results.
Nevertheless, several limitations should be noted. First, as largescale RCTs enrolled in our meta-analysis are limited, the internal
validity of our results should be careful interpretation. However, no
heterogeneity on hospital mortality was found, and our primary
finding was supported by further TSA. Second, because some
studies were not mentioned the severity of disease, the timing and
duration of enteral GLN administration, we could not explore the
impact of these factors on the clinical outcomes, which may
introducing potential heterogeneity. Third, lower baseline serum
GLN concentrations are in connection with higher mortality rate in
critical illness patients. Few trials in our study reported baseline
supplementation at any dosage and mortality. In a prior metaanalysis of enteral GLN therapy, García-de-Lorenzo et al. suggested intake of 20e30 g/d GLN, although the dosage and the
course of treatment varied greatly relying on the pathology [44].
Human researches showed that it is safe to supplement up to 0.5 g/
kg/d GLN [45], while a study suggested that GLN administration
greater than 0.5 g/kg/d increases mortality in patients with critically ill [39]. The underlying mechanism is unclear. One explanation
could be that effect is due to other immunomodulatory components or an interaction among those [16].
A meta-analysis of evaluating the impact of GLN-enriched
enteral supplementation in critical illness patients found that it
conferred no obvious benefit on hospital and ICU LOS [17]. Our
results demonstrated a beneficial role in critically ill patients of
reducing hospital LOS rather than ICU LOS, which was in line with
previously reported studies [16,40,46]. However, the significant
reduction of hospital LOS was driven largely by three trials of burn
patients in the study of van Zanten AR et al. [16], and evidence
supporting hospital LOS reduction was not of high quality [40,46].
Although favorable role was observed for hospital LOS, it should be
interpreted with caution as both ICU and hospital LOS can be
heavily influenced by organizational rather than medical factors.
Taking into account the infectious complications, there is sufficient evidence to support that maintaining enteral nutrition and
protecting gastrointestinal function are beneficial in severe patients
[47]. The results of prospective RCTs showed that enteral GLN was
associated with a lower infection [11,35]. However, consistent with
prior meta-analysis [16], our result suggested that the infectious
complications cloud not benefit from enteral GLN in critically ill
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Clinical Nutrition 43 (2024) 124e133
Fig. 6. The effect of enteral GLN on infectious complications; (A) Forest plot of infectious complications; (B) TSA for infectious complications.
serum GLN levels. Patients with below normal GLN level cannot
benefit from enteral GLN supplementation, however, this result
should be interpreted with caution due to small sample size.
2022A1515140138); Guangdong Provincial Hospital pharmacist
youth lifting research fund (Qingyue Pharmaceutical Fund)
(2023QNTJ39).
5. Conclusions
Ethics approval and consent to participate
Not applicable.
Our meta-analysis reveal that enteral GLN therapy could not
significantly ameliorate hospital mortality, ICU LOS and infectious
complications with the exception of decreasing hospital LOS among
patients critically ill, which were supported by TSA. No convincing
evidence supports that enteral GLN supplementation used
routinely in critical patients.
Consent for publication
All authors have read and agreed to the submission of the
manuscript.
Availability of data and materials
Conflicts of interest
All relevant data that support the findings of this study are
available in this article and its supplementary information.
The authors declare no competing interests.
Acknowledgements
Funding
BFL and JWS contributed equally to this work. BFL and JWS
carried out the study search, collected the data, evaluated the bias
and certainty of evidence, undertook the statistical analyses and
participated in drafting and editing the manuscript. BFL had
This study was supported by grants from National Natural Science
Foundation of China (82000842); Guangdong Basic and Applied
Basic Research Foundation (2021A1515010151, 2021B1515140054,
131
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Clinical Nutrition 43 (2024) 124e133
primary responsibility for final content. J.C. helped to search literature, extract the data and perform the statistical analysis. H.Q.S.
offered critical criteria for elemental intellectual features, interpreted data and did quality assessment. L.H.S. conceived the study,
guided clinical practice issues and revised the manuscript. B.C.X.
conceived and designed the study, analyzed the data and revised
the manuscript for important intellectual content. All authors read
and approved the final manuscript.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnu.2023.11.011.
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