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The Cochrane Database of Systematic... Sep 2022Chronic loss of appetite in cystic fibrosis concerns both individuals and families. Appetite stimulants have been used to help cystic fibrosis patients with chronic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic loss of appetite in cystic fibrosis concerns both individuals and families. Appetite stimulants have been used to help cystic fibrosis patients with chronic anorexia attain optimal body mass index (BMI) and nutritional status. However, these may have adverse effects on clinical status. This is an updated version of the original review.
OBJECTIVES
To systematically search for and evaluate the evidence on the beneficial effects of appetite stimulants in the management of cystic fibrosis-related anorexia and synthesise reports of any side effects.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register and online trials registries; handsearched reference lists; and contacted local and international experts to identify relevant trials. Last search of the Cystic Fibrosis Trials Register: 23 May 2022. Last search of online trial registries: 10 May 2022.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials of appetite stimulants compared to placebo, control, no treatment or different appetite stimulants, or to the same appetite stimulants at different doses or regimens for at least one month in adults and children with cystic fibrosis.
DATA COLLECTION AND ANALYSIS
Review authors independently extracted data and assessed risk of bias of the included trials. We used the GRADE approach to assess the certainty of the evidence and performed meta-analyses.
MAIN RESULTS
We included four trials (70 participants) comparing appetite stimulants (cyproheptadine hydrochloride and megestrol acetate) to placebo; the numbers of adults or children within each trial were not always reported. We assessed the certainty of evidence as low due to the small number of participants, incomplete or selective outcome reporting, and unclear risk of selection bias. Regarding our primary outcomes, a meta-analysis of two trials (42 participants) showed that appetite stimulants may produce a larger increase in weight (kg) at three months (mean difference (MD) 1.25 kg, 95% confidence interval (Cl) 0.45 to 2.05), and one trial (17 participants) showed a similar result at six months (MD 3.80 kg, 95% CI 1.27 to 6.33) (both low-certainty evidence). Results also showed that weight z score may increase with appetite stimulants compared to placebo at three months (MD 0.61, 95% CI 0.29 to 0.93; 3 studies; 40 participants; P < 0.001) and at six months (MD 0.74, 95% CI 0.26 to 1.22; 1 trial; 17 participants). There was no evidence of a difference in effect between cyproheptadine hydrochloride and megestrol acetate for either outcome. Only one trial (25 participants) reported analysable data for body composition (BMI), with results favouring cyproheptadine hydrochloride compared to placebo; a further trial (16 participants) narratively agreed with this result. All four trials reported on lung function at durations ranging from two to nine months. Considering analysable data, two trials (42 participants) found that appetite stimulants may make little or no difference in forced expiratory volume at one second (FEV) % predicted at three months, and one trial (17 participants) found similar results at six months. Two further three-month trials narratively agreed with these results. Limited information was reported for secondary outcomes. Two trials (23 participants) reported results showing that appetite stimulants may increase appetite compared to placebo at three months (odds ratio 45.25, 95% CI 3.57 to 573.33; low-certainty evidence). Only one study reported on quality of life, finding that cyproheptadine reduced fatigue in two participants compared with none with placebo. One study (25 participants) found no difference in energy intake between appetite stimulant or placebo at three months. Insufficient reporting of adverse effects prevented a full determination of their impact. Two studies (33 participants) narratively reported similar requirements for additional antibiotics between appetite stimulants and placebo at three months. AUTHORS' CONCLUSIONS: At six months in adults and children, appetite stimulants improved only two of the outcomes of this review: weight (or weight z score) and subjectively reported appetite. Insufficient reporting of side effects prevented a full determination of their impact. Whilst the data may suggest the potential use of appetite stimulants in treating anorexia in adults and children with cystic fibrosis, this is based upon low-certainty evidence from a small number of trials, therefore firm conclusions cannot be drawn. Clinicians need to be aware of the potential adverse effects of appetite stimulants and actively monitor any individuals prescribed these medications accordingly. Research is required to determine meaningful surrogate measures for appetite and to define what constitutes quality weight gain. Future trials of appetite stimulants should use a validated measure of symptoms including a disease-specific instrument for measuring poor appetite. This review highlights the need for multicentred, adequately powered, and well-designed trials to evaluate agents to safely increase appetite in people with cystic fibrosis and to establish the optimal mode of treatment.
Topics: Adult; Anorexia; Anti-Bacterial Agents; Appetite Stimulants; Child; Cyproheptadine; Cystic Fibrosis; Humans; Megestrol Acetate; Quality of Life
PubMed: 36149378
DOI: 10.1002/14651858.CD008190.pub3 -
Tuberculosis Research and Treatment 2023Prisoners in Sub-Saharan Africa (SSA) are at a high risk of tuberculosis (TB) infection due to overcrowding and poor ventilation. Consequently, TB is a leading cause of...
INTRODUCTION
Prisoners in Sub-Saharan Africa (SSA) are at a high risk of tuberculosis (TB) infection due to overcrowding and poor ventilation. Consequently, TB is a leading cause of morbidity and mortality in prison, and many inmates face a number of barriers to TB control and had limited information in the region. Thus, the aim of this systematic review and meta-analysis was to estimate the overall pooled prevalence of pulmonary TB and predictors among prison inmates in SSA.
METHODS
From 2006 to 2019, a systematic review and meta-analysis was conducted using various databases, including PubMed, Embase, Web of Science, and Scopus. The data were extracted in Microsoft Excel using a standardized data extraction format, and the analysis was carried out with STATA version 14. To detect heterogeneity across studies, the and the Cochrane test statistics were computed. To determine the overall prevalence of TB and predictors among prison populations, a random effect meta-analysis model was used.
RESULTS
Of the 3,479 retrieved articles, 37studies comprising 72,844 inmates met the inclusion criteria. The pooled prevalence of pulmonary TB among prison inmates in SSA was 7.74% (95% CI: 6.46-8.47). In the subgroup analysis, the highest prevalence was found in the Democratic Republic Congo (DRC) (19.72%) followed by Zambia (11.68%) and then Ethiopia (9.22%). TB/HIV coinfection (OR 4.99 (95% CI: 2.60-9.58)), Body mass index (BMI < 18.5) (OR 3.62 (95% CI: 2.65-6.49)), incarceration (OR 4.52 (95% CI: 2.31-5.68)), and previous TB exposure (OR 2.43 (95% CI: 1.61-3.56)) had higher odds of pulmonary TB among inmates.
CONCLUSION
The prevalence of pulmonary TB among SSA prison inmates was found to be high as compared to total population. TB/HIV coinfection, BMI, incarceration duration, and TB exposure were all predictors with pulmonary tuberculosis in prison inmates. As a result, emphasizing early screening for prisoners at risk of pulmonary TB is an important point to achieving global TB commitments in resource-limited settings.
PubMed: 37260437
DOI: 10.1155/2023/6226200 -
Journal of Vascular Surgery. Venous and... Jan 2024Data on complications after upper extremity vein thrombosis (UEVT) are limited and heterogeneous. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Data on complications after upper extremity vein thrombosis (UEVT) are limited and heterogeneous.
METHODS
The aim of the present study was to evaluate the pooled proportions of venous thromboembolism (VTE) recurrence, bleeding, and post-thrombotic syndrome (PTS) in patients with UEVT. A systematic literature review was conducted of PubMed, Embase, and the Cochrane Library databases from January 2000 to April 2023 in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. All studies included patients with UEVT and were published in English. Meta-analyses of VTE recurrence, bleeding, and of PTS after UEVT were performed to compute pooled estimates and associated 95% confidence intervals (CIs). Subgroup analyses of cancer-associated UEVT and catheter-associated venous thrombosis were conducted. Patients with Paget-Schroetter syndrome or effort thrombosis were excluded.
RESULTS
A total of 55 studies with 15,694 patients were included. The pooled proportions for VTE recurrence, major bleeding, and PTS were 4.8% (95% CI, 3.8%-6.2%), 3.0% (95% CI, 2.2%-4.0%), and 23.8% (95% CI, 17.0%-32.3%), respectively. The pooled proportion of VTE recurrence was 2.7% (95% CI, 1.6%-4.6%) for patients treated with direct oral anticoagulants (DOACs), 1.7% (95% CI, 0.8%-3.7%) for patients treated with low-molecular-weight heparin (LMWH), and 4.4% (95% CI, 1.5%-11.8%) for vitamin K antagonists (VKAs; P = .36). The pooled proportion was 6.3% (95% CI, 4.3%-9.1%) for cancer patients compared with 3.1% (95% CI, 2.1%-4.6%) for patients without cancer (P = .01). The pooled proportion of major bleeding for patients treated with DOACs, LMWH, and VKAs, was 2.1% (95% CI, 0.9%-5.1%), 3.2% (95% CI, 1.4%-7.2%), and 3.4% (95% CI, 1.4%-8.4%), respectively (P = .72). The pooled proportion of PTS for patients treated with DOACs, LMWH, and VKAs was 11.8% (95% CI, 6.5%-20.6%), 27.9% (95% CI, 20.9%-36.2%), and 24.5% (95% CI, 17.6%-33.1%), respectively (P = .02).
CONCLUSIONS
The results from this study suggest that UEVT is associated with significant rates of PTS and VTE recurrence. Treatment with DOACs might be associated with lower PTS rates than treatment with other anticoagulants.
Topics: Humans; Heparin, Low-Molecular-Weight; Venous Thromboembolism; Incidence; Vitamin K; Anticoagulants; Hemorrhage; Postthrombotic Syndrome; Upper Extremity Deep Vein Thrombosis; Neoplasms; Upper Extremity
PubMed: 37717788
DOI: 10.1016/j.jvsv.2023.09.002 -
Scientific Reports May 2023This systematic review and meta-analysis aimed to comprehensively evaluate the factors associated with mortality and progressive disease in NTM-LD patients. We conducted... (Meta-Analysis)
Meta-Analysis
This systematic review and meta-analysis aimed to comprehensively evaluate the factors associated with mortality and progressive disease in NTM-LD patients. We conducted a literature search to identify the eligible studies, dated between January 1, 2007, and April 12, 2021. Forty-one studies with total 10,452 patients were included. The overall all-cause mortality rate was 20% (95% CI 17-24%). The overall rates of clinical and radiographic progressive disease were 46% (95% CI 39-53%) and 43% (95% CI 31-55%), respectively. Older age, male sex, history of TB, diabetes, chronic heart disease, malignancy, systemic immunosuppression, chronic liver disease, presence of cavity, consolidative radiologic features, acid-fast bacillus (AFB) smear positivity, hypoalbuminemia, anemia, increasing platelet count, high CRP, and high ESR were significantly associated with increased all-cause mortality, whereas increasing body mass index (BMI), hemoptysis, and treatment with rifamycin regimen (in M. xenopi) were significantly associated with decreased all-cause mortality in multivariable analysis. History of TB, Aspergillus co-infection, cough, increased sputum, weight loss, presence of cavity, and AFB smear positivity were significantly associated with increased clinical progression with treatment, while older age and low BMI were significantly associated with decreased clinical progression in multivariable analysis. Older age, interstitial lung disease, presence of cavity, consolidative radiologic feature, anemia, high CRP, and leukocytosis were significantly associated with increased radiographic progression after adjusting for covariates. Older age, history of tuberculosis, presence of cavity, consolidative radiologic features, AFB smear positivity, anemia, and high C-reactive protein were common significant factors associated with the all-cause mortality and clinical or radiographic progressive disease of NTM-LD. These factors are thought to directly affect NTM-LD related mortality. The future prediction models for the prognosis of NTM-LD should be established considering these factors.
Topics: Humans; Male; Retrospective Studies; Mycobacterium Infections, Nontuberculous; Lung Diseases; Pneumonia; Disease Progression
PubMed: 37147519
DOI: 10.1038/s41598-023-34576-z -
Chinese Medical Journal Dec 2015Malnutrition and tuberculosis (TB) tend to interact with each other. TB may lead to nutrition deficiencies that will conversely delay recovery by depressing immune... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Malnutrition and tuberculosis (TB) tend to interact with each other. TB may lead to nutrition deficiencies that will conversely delay recovery by depressing immune functions. Nutrition support can promote recovery in the subject being treated for TB. The aim of this study was to evaluate the effectiveness of nutrition support on promoting the recovery of adult pulmonary TB patients with anti-TB drug therapy.
METHODS
English database of the Cochrane Controlled Trials Register, PubMed, EMBASE, and Chinese database of CBM, CNKI, VIP, and WANFANG were searched. Randomized controlled trials comparing nutrition support (given for more than 2 weeks) with no nutrition intervention, nutrition advice only, or placebo-control for TB patients being anti-TB treated were included. Two reviewers conducted data extraction, assessed the quality of the studies independently, and any discrepancies were solved by the third reviewer. Data were entered and analyzed by RevMan 5.2 software, and meta-analysis was done using risk ratios (RR s) for dichotomous variables and mean differences (MDs) for continuous variables with 95% confidence intervals (CI s).
RESULTS
A total of 19 studies (3681 participants) were included. In nutritional support for TB patients, pooled RR and its 95% CI of sputum smears- or culture-negative conversion rate and chest X-ray (CXR) absorption rate were 1.10 (1.04, 1.17) and 1.22 (1.08, 1.39), respectively, the pooled MD and its 95% CI of body mass index (BMI) and time of sputum smears or culture negativity were 0.59 (0.16, 1.2) and - 5.42 (-7.93, -2.92), respectively, compared with the control group. The differences in outcomes of CXR zone affected, TB score, serum albumin, and hemoglobin were not statistically significant (P = 0.76, 0.24, 0.28, and 0.20, respectively) between the intervention group and the control group. No systemic adverse events were recorded.
CONCLUSIONS
During anti-TB course, nutrition support may be helpful in treatment of TB patients by improving both sputum smears- or culture-negative conversion rate and BMI, shortening the time of sputum conversion negative. Whether it can improve the final clinical effect, there still needs high-level quality studies to confirm in the future.
Topics: Animals; Antitubercular Agents; Humans; Malnutrition; Nutritional Support; Sputum; Tuberculosis, Pulmonary
PubMed: 26612299
DOI: 10.4103/0366-6999.170255 -
ESC Heart Failure Oct 2021Takotsubo cardiomyopathy (TCM), characterized by reversible ventricular dysfunction, has similar mortality to acute coronary syndrome. With the growing interest in the... (Review)
Review
Takotsubo cardiomyopathy (TCM), characterized by reversible ventricular dysfunction, has similar mortality to acute coronary syndrome. With the growing interest in the diagnosis of and interventions for TCM, many risk factors had been found to affect the prognosis of TCM patients, such as age, sex, and pre-existing diseases. Because of the incomplete understanding of the pathophysiologic mechanism in TCM, evidence-based medical therapy for this condition is lacking. Early intervention on risk factors may improve the outcomes of TCM. In this review, we sought to provide up-to-date evidence on risk factors and medical therapies that affect TCM outcome. We found that male sex, physical triggers, and certain comorbidities such as chronic kidney disease, malignant disease, higher body mass index, sepsis, chronic obstructive pulmonary disease, and anaemia were associated with poor TCM prognosis. In contrast, race, hyperlipidaemia, diabetes mellitus, and mood disorders were not clearly associated with TCM prognosis. We also reviewed the effect of medical therapies on TCM outcome, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, calcium channel blockers, and statins. The evidence that these medications confer a survival benefit on TCM patients is limited. Understanding these prognostic factors could help develop risk-stratification tools for TCM and establish effective prevention and interventions for this not-so-benign condition. Further multicentre clinical studies with large samples and meta-analyses of findings from previous studies are needed to address the inconsistent findings among the many potential risk factors for TCM.
Topics: Body Mass Index; Comorbidity; Humans; Male; Prognosis; Risk Factors; Takotsubo Cardiomyopathy
PubMed: 34374223
DOI: 10.1002/ehf2.13531 -
Journal of Vascular Surgery Apr 2017Obesity has been associated with an increased risk for cardiovascular morbidity and mortality, although pooled evidence in patients undergoing vascular surgery are... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Obesity has been associated with an increased risk for cardiovascular morbidity and mortality, although pooled evidence in patients undergoing vascular surgery are lacking. The aim of this systematic review was to evaluate the effect of body mass index (BMI) on major postoperative outcomes in patients undergoing vascular surgery.
METHODS
A systematic literature review conforming to established criteria to identify eligible articles published before May 2016 was conducted. Eligible studies evaluated major postoperative outcomes in vascular surgery patients of different BMI groups according to the weight classification of the National Institutes of Health criteria: underweight (UW), BMI ≤18.5 kg/m; normal weight (NW), BMI of 18.6 to 24.9 kg/m; overweight (OW), BMI of 25 to 29.9 kg/m; and obese (OB), BMI ≥30 kg/m. Major outcomes included 30-day mortality, cardiac complications, and respiratory complications. Secondary outcomes included wound and cerebrovascular complications, renal complications, deep venous thrombosis/pulmonary embolism, and other complications.
RESULTS
Overall, eight retrospective studies were eligible including a total of 92,525 vascular surgery patients (2223 UW patients, 29,727 NW patients, 34,517 OW patients, and 26,058 OB patients). Pooled data were as follows: mortality rate, 2.5%; cardiac events, 2.1%; respiratory events, 8.6%; wound complications, 6.4%; cerebrovascular events, 6.4%; renal complications, 3.9%; other infections, 5.3%; deep venous thrombosis/pulmonary embolism, 1.2%; and other complications, 3.7%. Meta-analysis showed that OB patients were associated with lower mortality (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.541-0.757; P < .0001), cardiac morbidity (OR, 0.81; 95% CI, 0.708-0.938; P = .004), and respiratory morbidity (OR, 0.87; 95% CI, 0.802-0.941; P = .0006) after vascular surgery compared with NW patients. However, OB patients were associated with a higher wound complication rate (OR, 2.39; 95% CI, 1.777-3.211; P < .0001) compared with NW patients. In contrast, UW patients were associated with a higher mortality (OR, 1.71; 95% CI, 1.177-2.505; P = .005) and respiratory morbidity (OR, 1.84; 95% CI, 1.554-2.166; P < .0001) compared with NW patients.
CONCLUSIONS
The "obesity paradox" does exist in patients undergoing vascular surgery. This paradox refers not only to 30-day overall mortality but also to 30-day cardiac and respiratory complications. However, obesity seems to be associated with more wound complications. Surprisingly, UW patients are associated with higher mortality as well as respiratory events postoperatively.
Topics: Aged; Body Mass Index; Chi-Square Distribution; Female; Humans; Male; Middle Aged; Obesity; Odds Ratio; Postoperative Complications; Protective Factors; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vascular Diseases; Vascular Surgical Procedures
PubMed: 27876519
DOI: 10.1016/j.jvs.2016.09.032 -
Sleep Medicine Reviews Oct 2023Despite substantial disease burden, existing evidence on the risk factors for obstructive sleep apnea (OSA) have been derived primarily from cross-sectional studies... (Review)
Review
Despite substantial disease burden, existing evidence on the risk factors for obstructive sleep apnea (OSA) have been derived primarily from cross-sectional studies without determining temporality. Therefore, we aimed to systematically synthesize the literature on longitudinal risk factors for sleep study-assessed OSA and questionnaire-assessed probable OSA from cohort studies in the general adult population settings. We systematically searched Embase and Medline (on OVID) databases. Eleven studies met the inclusion criteria. Meta-analyses were not conducted due to methodological heterogeneity of exposure and outcome measurements. There was consistent evidence that weight gain was associated with incident (n = 2) and greater severity (n = 2) of OSA. One study each observed an association of higher baseline body-mass index, male sex, asthma, a specific genetic polymorphism in rs12415421, and insulin resistance/hyperglycemia, with incident OSA. Long-term exposure to ambient air pollution (NO, n = 1) was associated with OSA, and menopausal transitions (n = 1) with higher apnea-hypopnea index. There were no eligible studies on long-term smoking or alcohol use. In conclusion, approximately 10% increase in weight, especially in males, might alert clinicians to consider potential or worsening OSA. Large, well-designed longitudinal studies are needed to consolidate knowledge on other associations with OSA development, especially on potentially modifiable risk factors.
PubMed: 37639973
DOI: 10.1016/j.smrv.2023.101838 -
International Journal of Chronic... 2016In recent years, the pleiotropic roles of vitamin D have been highlighted in various diseases. However, the association between serum vitamin D and COPD is not well... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In recent years, the pleiotropic roles of vitamin D have been highlighted in various diseases. However, the association between serum vitamin D and COPD is not well studied. This updated systematic review and meta-analysis aimed to assess the relationship between vitamin D and the risk, severity, and exacerbation of COPD.
METHODS
A systematic literature search was conducted in PubMed, Medline, EMBASE, Chinese National Knowledge Infrastructure, Wanfang, and Weipu databases. The pooled risk estimates were standardized mean difference (SMD) with 95% confidence interval (CI) for vitamin D levels and odds ratio (OR) with 95% CI for vitamin D deficiency. Meta-regression and subgroup analyses were performed on latitude, body mass index, and assay method.
RESULTS
A total of 21 studies, including 4,818 COPD patients and 7,175 controls, were included. Meta-analysis showed that lower serum vitamin D levels were found in COPD patients than in controls (SMD: -0.69, 95% CI: -1.00, -0.38, <0.001), especially in severe COPD (SMD: -0.87, 95% CI: -1.51, -0.22, =0.001) and COPD exacerbation (SMD: -0.43, 95% CI: -0.70, -0.15, =0.002). Vitamin D deficiency was associated with increased risk of COPD (OR: 1.77, 95% CI: 1.18, 2.64, =0.006) and with COPD severity (OR: 2.83, 95% CI: 2.00, 4.00, <0.001) but not with COPD exacerbation (OR: 1.17, 95% CI: 0.86, 1.59, =0.326). Assay methods had significant influence on the heterogeneity of vitamin D deficiency and COPD risk.
CONCLUSION
Serum vitamin D levels were inversely associated with COPD risk, severity, and exacerbation. Vitamin D deficiency is associated with increased risk of COPD and severe COPD but not with COPD exacerbation. It is worth considering assay methods in the heterogeneity sources analysis of association between vitamin D deficiency and COPD.
Topics: Biomarkers; Case-Control Studies; Dietary Supplements; Disease Progression; Humans; Lung; Odds Ratio; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Risk Factors; Severity of Illness Index; Vitamin D; Vitamin D Deficiency
PubMed: 27799758
DOI: 10.2147/COPD.S101382 -
Frontiers in Medicine 2022Testosterone deficiency is common in chronic obstructive pulmonary disease (COPD) patients. There has been a growing interest in the potential use of anabolic-androgenic...
BACKGROUND
Testosterone deficiency is common in chronic obstructive pulmonary disease (COPD) patients. There has been a growing interest in the potential use of anabolic-androgenic steroids (AASs) in patients with COPD recently. However, whether AASs could improve their clinical outcomes remains unknown.
METHODS
In order to explore the efficacy of AASs in patients with COPD, systematic search of MEDLINE, Embase, the Cochrane Library and ClinicalTrials.gov for randomized controlled trials (RCTs) of AASs for COPD published before March 17, 2022 was performed.
RESULTS
Data were extracted from 8 articles involving 520 participants. The median number of participants per study was 39.5 and the mean follow up was 14.2 weeks. As compared to the control group, AASs therapy could significantly improve body weight (weighted mean difference (WMD), 1.38 kg; 95% CI, 0.79 to 1.97 kg), fat-free mass (WMD, 1.56 kg; 95% CI, 0.94 to 2.18 kg) and peak workload (WMD, 6.89W; 95% CI, 3.97 to 9.81W) of COPD patients, but no improvements in spirometry indicators and six-minute walking distances (WMD, 16.88 m; 95%, -3.27 to 37.04 m). Based on the available research data, it is uncertain whether AASs treatment could improve the quality of life of COPD patients.
CONCLUSIONS
Limited published evidence indicates that AASs therapy provides clinical benefits in patients with COPD. However, longer and larger studies are needed to better clarify the efficacy of AASs and draw final conclusions.
PubMed: 36148458
DOI: 10.3389/fmed.2022.915159