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Medicine Feb 2017Both oral sucrose (OS) and nonnutritive sucking (NNS) are effective nonpharmacological methods to alleviate procedures pain in neonatal intensive care unit (NICU)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Both oral sucrose (OS) and nonnutritive sucking (NNS) are effective nonpharmacological methods to alleviate procedures pain in neonatal intensive care unit (NICU) newborns when they were used alone, but the combined effect of OS+NNS remains controversial. So, we conducted this study to evaluate the efficiency of NNS combined with oral sucrose on pain relief in NICU newborns undergoing painful procedures.
METHODS
We searched PubMed, Ovid (Medline), Embase (Medline), Cochrane Central Library, and other resources such as Google Scholar, bibliographies of included literatures for all available articles. Two reviewers screened literatures and extracted data independently. The fixed effects model was used to pool the results using Reviewer Manager (RevMan) 5.3. As each study included in our meta-analysis had been approved by Ethics Committee or institutional review board, thus our study did not need ethical approval.
RESULTS
Seven randomized controlled trials, including 599 participants, were contained in our meta-analysis. The combination of oral sucrose and NNS is associated with reduced pain scores (mean difference [MD], -0.52; 95% confidence interval [CI], -0.68 to -0.36); shortened crying time (MD,-0.92; 95% CI, -1.39 to -0.44); but the 2 groups did not differ significantly in reducing bradycardia (MD, 0.73; 95% CI, 0.32-1.68), tachycardia (MD, 0.65; 95% CI, 0.38-1.10), or desaturations (MD, 0.73; 95% CI, 0.32-1.68).
CONCLUSION
The pooled evidence indicates that the combination measures may serve as an evidence-based guideline for pain relief among patients having minor pain. Besides, it also indicates that OS combined with NNS can be an alternative for better prevention and management of procedure pain in NICU newborns. Nevertheless, the results may be limited due to incomplete data, and thus, more randomized controlled trials or well-designed studies are required to determine the effects of OS+NNS in the future.
Topics: Crying; Humans; Intensive Care Units, Neonatal; Pain Management; Sucking Behavior; Sucrose
PubMed: 28178172
DOI: 10.1097/MD.0000000000006108 -
Nutrients Jul 2019and are highly abundant human gut microbes in healthy individuals, and reduced levels are associated with inflammation and alterations of metabolic processes involved...
and are highly abundant human gut microbes in healthy individuals, and reduced levels are associated with inflammation and alterations of metabolic processes involved in the development of type 2 diabetes. Dietary factors can influence the abundance of and , but the evidence is not clear. We systematically searched PubMed and Embase to identify clinical trials investigating any dietary intervention in relation to and . Overall, 29 unique trials were included, of which five examined 19 examined , and six examined both, in a total of 1444 participants. A caloric restriction diet and supplementation with pomegranate extract, resveratrol, polydextrose, yeast fermentate, sodium butyrate, and inulin increased the abundance of , while a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols decreased the abundance of . For , the main studied intervention was prebiotics (e.g. fructo-oligosaccharides, inulin type fructans, raffinose); seven studies reported an increase after prebiotic intervention, while two studies reported a decrease, and four studies reported no difference. Current evidence suggests that some dietary factors may influence the abundance of and However, more research is needed to support these microflora strains as targets of microbiome shifts with dietary intervention and their use as medical nutrition therapy in prevention and management of chronic disease.
Topics: Akkermansia; Diet; Faecalibacterium prausnitzii; Gastrointestinal Microbiome; Humans; Verrucomicrobia
PubMed: 31336737
DOI: 10.3390/nu11071565 -
BMJ Open Oct 2016To examine patterns of energy drink consumption by children and young people, attitudes towards these drinks, and any associations with health or other outcomes. (Review)
Review
OBJECTIVE
To examine patterns of energy drink consumption by children and young people, attitudes towards these drinks, and any associations with health or other outcomes.
DESIGN
Rapid evidence assessment and narrative synthesis.
DATA SOURCES
9 electronic bibliographic databases, reference lists of relevant studies and searches of the internet.
RESULTS
A total of 410 studies were located, with 46 meeting the inclusion criteria. The majority employed a cross-sectional design, involved participants aged 11-18 years, and were conducted in North America or Europe. Consumption of energy drinks by children and young people was found to be patterned by gender, with boys consuming more than girls, and also by activity levels, with the highest consumption observed in the most and least sedentary individuals. Several studies identified a strong, positive association between the use of energy drinks and higher odds of health-damaging behaviours, as well as physical health symptoms such as headaches, stomach aches, hyperactivity and insomnia. There was some evidence of a dose-response effect. 2 experimental studies involving small numbers of junior athletes demonstrated a positive impact on limited aspects of sports performance. 3 themes emerged from the qualitative studies: reasons for use; influences on use; and perceived efficacy and impact. Taste and energy-seeking were identified as key drivers, and branding and marketing were highlighted as major influences on young people's consumption choices. Awareness of possible negative effects was low.
CONCLUSIONS
There is growing evidence that consumption of energy drinks is associated with a range of adverse outcomes and risk behaviours in terms of children's health and well-being. However, taste, brand loyalty and perceived positive effects combine to ensure their popularity with young consumers. More research is needed to explore the short-term and long-term impacts in all spheres, including health, behaviour and education.
TRIAL REGISTRATION NUMBER
CRD42014010192.
Topics: Adolescent; Caffeine; Carbonated Beverages; Child; Choice Behavior; Consumer Behavior; Cross-Sectional Studies; Dietary Sucrose; Energy Drinks; Energy Intake; Europe; Health Behavior; Health Knowledge, Attitudes, Practice; Humans; North America; Qualitative Research; Sex Distribution
PubMed: 27855083
DOI: 10.1136/bmjopen-2015-010380 -
Pain May 2022Many analgesics inadequately address the psychiatric comorbidities of chronic and persistent pain, but there is no standard preclinical model of pain-altered behavior to... (Meta-Analysis)
Meta-Analysis
Many analgesics inadequately address the psychiatric comorbidities of chronic and persistent pain, but there is no standard preclinical model of pain-altered behavior to support the development of new therapies. To explore this conflicting and inconclusive literature, we conducted a focused systematic review and meta-analysis on the effect of complete Freund adjuvant-induced (CFA) rodent hind paw inflammation on multiple classical indicators of exploratory behavior, stress coping, and naturalistic behavior. Our primary objective was to define CFA's effect on assays including, but not limited to, the elevated plus maze and forced swim test. Our secondary objective was to discover how variables such as species and strain may influence outcomes in such assays. We searched Ovid MEDLINE, Embase, Scopus, and Web of Science in April and October 2020 for studies with adult rodents injected with CFA into the hind paw and subsequently tested for aspects of "anxiety-like" or "depressive-like" behaviors. Forty-four studies evaluated performance in the elevated plus or zero maze, open field test, light-dark box, place escape and avoidance paradigm, forced swim test, tail suspension test, sucrose preference test, wheel running, and burrowing assay. Complete Freund adjuvant modestly but significantly decreased exploratory behavior, significantly increased passive stress coping in the tail suspension test but not the forced swim test, and significantly decreased preference for sucrose and naturally rewarding activity. Subgroup analyses revealed significant differences between species and animal sourcing. Based on the evidence provided here, we conclude future studies should focus on CFA's effect on natural rewards and naturalistic behaviors.
Topics: Animals; Behavior, Animal; Disease Models, Animal; Freund's Adjuvant; Motor Activity; Pain; Rodentia; Sucrose
PubMed: 34510137
DOI: 10.1097/j.pain.0000000000002467 -
Sports Medicine (Auckland, N.Z.) Jan 2021Exercise appears to cause damage to the endothelial lining of the human gastrointestinal tract and elicit a significant increase in gut permeability. (Meta-Analysis)
Meta-Analysis
AIM
Exercise appears to cause damage to the endothelial lining of the human gastrointestinal tract and elicit a significant increase in gut permeability.
OBJECTIVE
The aim of this review was to determine the effect of an acute bout of exercise on gut damage and permeability outcomes in healthy populations using a meta-analysis.
METHODS
PubMed, The Cochrane Library as well as MEDLINE, SPORTDiscus and CINHAL, via EBSCOhost were searched through February 2019. Studies were selected that evaluated urinary (ratio of disaccharide/monosaccharide excretion) or plasma markers [intestinal Fatty Acid Binding Protein (i-FABP)] of gut permeability and gut cell damage in response to a single bout of exercise.
RESULTS
A total of 34 studies were included. A random-effects meta-analysis was performed, and showed a large and moderate effect size for markers of gut damage (i-FABP) (ES 0.81; 95% CI 0.63-0.98; n = 26; p < 0.001) and gut permeability (Disaccharide Sugar/Monosaccharide Sugar) (ES 0.70; 95% CI 0.29-1.11; n = 17; p < 0.001), respectively. Exercise performed in hot conditions (> 23 °C) further increased markers of gut damage compared with thermoneutral conditions [ES 1.06 (95% CI 0.88-1.23) vs. 0.66 (95% CI 0.43-0.89); p < 0.001]. Exercise duration did not have any significant effect on gut damage or permeability outcomes.
CONCLUSIONS
These findings demonstrate that a single bout of exercise increases gut damage and gut permeability in healthy participants, with gut damage being exacerbated in hot environments. Further investigation into nutritional strategies to minimise gut damage and permeability after exercise is required. PROSPERO database number (CRD42018086339).
Topics: Biomarkers; Disaccharides; Exercise; Gastrointestinal Tract; Humans; Permeability
PubMed: 33201454
DOI: 10.1007/s40279-020-01348-y -
Nutrition Reviews Jan 2016The effect of added sugar intake on ectopic fat accumulation is a subject of debate. (Meta-Analysis)
Meta-Analysis Review
CONTEXT
The effect of added sugar intake on ectopic fat accumulation is a subject of debate.
OBJECTIVE
A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to examine the potential effect of added sugar intake on ectopic fat depots.
DATA SOURCES
MEDLINE, CAB Abstracts, CAB Global Health, and EBM (Evidence-Based Medicine) Reviews - Cochrane Central Register of Controlled Trials databases were searched for studies published from 1973 to September 2014.
DATA EXTRACTION
RCTs with a minimum of 6 days' duration of added sugar exposure in the intervention group were selected. The dosage of added sugar intake as a percentage of total energy was extracted or calculated. Means and standard deviations of pre- and post-test measurements or changes in ectopic fat depots were collected.
DATA SYNTHESIS
Fourteen RCTs were included. Most of the studies had a medium to high risk of bias. Meta-analysis showed that, compared with eucaloric controls, subjects who consumed added sugar under hypercaloric conditions likely increased ectopic fat, particularly in the liver (pooled standardized mean difference = 0.9 [95%CI, 0.6-1.2], n = 6) and muscles (pooled SMD = 0.6 [95%CI, 0.2-1.0], n = 4). No significant difference was observed in liver fat, visceral adipose tissue, or muscle fat when isocaloric intakes of different sources of added sugars were compared.
CONCLUSIONS
Data from a limited number of RCTs suggest that excess added sugar intake under hypercaloric diet conditions likely increases ectopic fat depots, particularly in the liver and in muscle fat. There are insufficient data to compare the effect of different sources of added sugars on ectopic fat deposition or to compare intake of added sugar with intakes of other macronutrients. Future well-designed RCTs with sufficient power and duration are needed to address the role of sugars on ectopic fat deposition.
Topics: Adipose Tissue; Choristoma; Diet; Dietary Sucrose; Energy Intake; Feeding Behavior; Humans; Liver; Monosaccharides; Muscles
PubMed: 26518034
DOI: 10.1093/nutrit/nuv047 -
Journal of Gastrointestinal and Liver... Apr 2023Transjugular intrahepatic portosystemic shunt (TIPS) is often used in patients with cirrhosis to manage portal hypertension-related complications. Unfortunately, 35-50%... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Transjugular intrahepatic portosystemic shunt (TIPS) is often used in patients with cirrhosis to manage portal hypertension-related complications. Unfortunately, 35-50% of patients develop overt hepatic encephalopathy (HE) after TIPS. However, data on lactulose and rifaximin to prevent post-TIPS HE is limited. Therefore, we aimed to perform a network meta-analysis to investigate the efficacy of multiple pharmacological regimens in the prevention of post-TIPS HE.
METHODS
A comprehensive search strategy to identify reports of studies of rifaximin use on post-TIPS hepatic encephalopathy was constructed using truncated keywords, phrases, and subject headings developed in Embase. This strategy was translated to MEDLINE, Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection, with all searches performed on 10 February 2022. No publication date or language limits were used.
RESULTS
The initial search identified 72 studies, and 56 studies were screened after removing duplicates. Five studies, two randomized controlled trials (RCTs) and three retrospective studies, met our inclusion criteria and were included in the final analysis. A total of 840 patients were included, with 65% male. Our meta- analysis did not find a statistically significant difference between lactulose vs placebo/no prophylaxis, nor rifaximin vs placebo/no prophylaxis, nor rifaximin plus lactulose vs placebo/no prophylaxis in the reduction of post-TIPS HE.
CONCLUSIONS
Rifaximin alone, lactulose alone, and rifaximin plus lactulose did not significantly reduce the development of post-TIPS HE. Based on the P-scores of the three treatment groups, the combination of rifaximin plus lactulose showed the most promising trend towards preventing post-TIPS HE. More studies, especially large RCTs, are warranted.
Topics: Male; Humans; Female; Hepatic Encephalopathy; Lactulose; Rifaximin; Network Meta-Analysis; Liver Cirrhosis
PubMed: 37004220
DOI: 10.15403/jgld-4508 -
The Cochrane Database of Systematic... Jun 2018Upper gastrointestinal (GI) bleeding due to stress ulcers contributes to increased morbidity and mortality in people admitted to intensive care units (ICUs). Stress... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Upper gastrointestinal (GI) bleeding due to stress ulcers contributes to increased morbidity and mortality in people admitted to intensive care units (ICUs). Stress ulceration refers to GI mucosal injury related to the stress of being critically ill. ICU patients with major bleeding as a result of stress ulceration might have mortality rates approaching 48.5% to 65%. However, the incidence of stress-induced GI bleeding in ICUs has decreased, and not all critically ill patients need prophylaxis. Stress ulcer prophylaxis can result in adverse events such as ventilator-associated pneumonia; therefore, it is necessary to evaluate strategies that safely decrease the incidence of GI bleeding.
OBJECTIVES
To assess the effect and risk-benefit profile of interventions for preventing upper GI bleeding in people admitted to ICUs.
SEARCH METHODS
We searched the following databases up to 23 August 2017, using relevant search terms: MEDLINE; Embase; the Cochrane Central Register of Controlled Trials; Latin American Caribbean Health Sciences Literature; and the Cochrane Upper Gastrointestinal and Pancreatic Disease Group Specialised Register, as published in the Cochrane Library (2017, Issue 8). We searched the reference lists of all included studies and those from relevant systematic reviews and meta-analyses to identify additional studies. We also searched the World Health Organization International Clinical Trials Registry Platform search portal and contacted individual researchers working in this field, as well as organisations and pharmaceutical companies, to identify unpublished and ongoing studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and quasi-RCTs with participants of any age and gender admitted to ICUs for longer than 48 hours. We excluded studies in which participants were admitted to ICUs primarily for the management of GI bleeding and studies that compared different doses, routes, and regimens of one drug in the same class because we were not interested in intraclass effects of drugs.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures as recommended by Cochrane.
MAIN RESULTS
We identified 2292 unique records.We included 129 records reporting on 121 studies, including 12 ongoing studies and two studies awaiting classification.We judged the overall risk of bias of two studies as low. Selection bias was the most relevant risk of bias domain across the included studies, with 78 studies not clearly reporting the method used for random sequence generation. Reporting bias was the domain with least risk of bias, with 12 studies not reporting all outcomes that researchers intended to investigate.Any intervention versus placebo or no prophylaxisIn comparison with placebo, any intervention seems to have a beneficial effect on the occurrence of upper GI bleeding (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.57; moderate certainty of evidence). The use of any intervention reduced the risk of upper GI bleeding by 10% (95% CI -12.0% to -7%). The effect estimate of any intervention versus placebo or no prophylaxis with respect to the occurrence of nosocomial pneumonia, all-cause mortality in the ICU, duration of ICU stay, duration of intubation (all with low certainty of evidence), the number of participants requiring blood transfusions (moderate certainty of evidence), and the units of blood transfused was consistent with benefits and harms. None of the included studies explicitly reported on serious adverse events.Individual interventions versus placebo or no prophylaxisIn comparison with placebo or no prophylaxis, antacids, H2 receptor antagonists, and sucralfate were effective in preventing upper GI bleeding in ICU patients. Researchers found that with H2 receptor antagonists compared with placebo or no prophylaxis, 11% less developed upper GI bleeding (95% CI -0.16 to -0.06; RR 0.50, 95% CI 0.36 to 0.70; 24 studies; 2149 participants; moderate certainty of evidence). Of ICU patients taking antacids versus placebo or no prophylaxis, 9% less developed upper GI bleeding (95% CI -0.17 to -0.00; RR 0.49, 95% CI 0.25 to 0.99; eight studies; 774 participants; low certainty of evidence). Among ICU patients taking sucralfate versus placebo or no prophylaxis, 5% less had upper GI bleeding (95% CI -0.10 to -0.01; RR 0.53, 95% CI 0.32 to 0.88; seven studies; 598 participants; moderate certainty of evidence). The remaining interventions including proton pump inhibitors did not show a significant effect in preventing upper GI bleeding in ICU patients when compared with placebo or no prophylaxis.Regarding the occurrence of nosocomial pneumonia, the effects of H2 receptor antagonists (RR 1.12, 95% CI 0.85 to 1.48; eight studies; 945 participants; low certainty of evidence) and of sucralfate (RR 1.33, 95% CI 0.86 to 2.04; four studies; 450 participants; low certainty of evidence) were consistent with benefits and harms when compared with placebo or no prophylaxis. None of the studies comparing antacids versus placebo or no prophylaxis provided data regarding nosocomial pneumonia.H2 receptor antagonists versus proton pump inhibitorsH2 receptor antagonists and proton pump inhibitors are most commonly used in practice to prevent upper GI bleeding in ICU patients. Proton pump inhibitors significantly more often prevented upper GI bleeding in ICU patients compared with H2 receptor antagonists (RR 2.90, 95% CI 1.83 to 4.58; 18 studies; 1636 participants; low certainty of evidence). When taking H2 receptor antagonists, 4.8% more patients might experience upper GI bleeding (95% CI 2.1% to 9%). Nosocomial pneumonia occurred in similar proportions of participants taking H2 receptor antagonists and participants taking proton pump inhibitors (RR 1.02, 95% CI 0.77 to 1.35; 10 studies; 1256 participants; low certainty of evidence).
AUTHORS' CONCLUSIONS
This review shows that antacids, sucralfate, and H2 receptor antagonists might be more effective in preventing upper GI bleeding in ICU patients compared with placebo or no prophylaxis. The effect estimates of any treatment versus no prophylaxis on nosocomial pneumonia were consistent with benefits and harms. Evidence of low certainty suggests that proton pump inhibitors might be more effective than H2 receptor antagonists. Therefore, patient-relevant benefits and especially harms of H2 receptor antagonists compared with proton pump inhibitors need to be assessed by larger, high-quality RCTs to confirm the results of previously conducted, smaller, and older studies.
Topics: Anti-Ulcer Agents; Blood Transfusion; Cause of Death; Histamine H2 Antagonists; Humans; Intensive Care Units; Length of Stay; Peptic Ulcer Hemorrhage; Pneumonia; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Selection Bias; Stress, Psychological; Sucralfate
PubMed: 29862492
DOI: 10.1002/14651858.CD008687.pub2 -
The American Journal of Clinical... Apr 2021Lack of robust estimates of human-milk nutrient composition and influential maternal factors, such as body composition, are barriers to informing nutrition policies and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Lack of robust estimates of human-milk nutrient composition and influential maternal factors, such as body composition, are barriers to informing nutrition policies and programs.
OBJECTIVE
The objective was to understand the relation between maternal BMI and human-milk energy, fat, and/or total protein.
METHODS
Four electronic databases (MEDLINE, Embase, CINAHL, and Web of Science) were searched. Outcomes assessed were human-milk energy (kcal/L), fat (g/L), and total protein (g/L) from mothers 1 to 6 mo postpartum. Studies with data on maternal BMI or weight and height that quantified human-milk energy, fat, or protein between 1 and 6 mo postpartum were eligible. Random-effects meta-regression weighted by the inverse of the study-level SE was completed for each of the 3 outcomes. The certainty of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.
RESULTS
A total of 11,373 titles and abstracts were identified, and after full-text screening, 69 articles of 66 studies were included. Meta-regression results showed a positive association between maternal BMI and human-milk fat (β: 0.56 g/L; 95% CI: 0.034, 1.1; P = 0.04; I2 = 93.7%, n = 63 datapoints). There was no significant association between maternal BMI and human-milk energy (β: 3.9 kcal/L; 95% CI: -1.6, 9.5; P = 0.16, I2 = 93.3%, n = 40 datapoints) or total protein (β: 0.13 g/L; 95% CI: -0.16, 0.41; P = 0.37, I2 = 99.1%, n = 40 datapoints). The certainty of evidence for human-milk energy was low and the certainty of evidence for fat and total protein was very low.
CONCLUSIONS
Meta-regression analysis of available literature suggested an association between maternal BMI and human-milk fat between 1 and 6 mo postpartum. Future studies are needed to confirm the relation between maternal BMI; variation in human-milk energy, fat, and protein content; and the implications for child growth and development. This review is registered with International Prospective Register of Systematic Reviews (PROSPERO 2018 CRD42018098808) at https://www.crd.york.ac.uk/prospero/.
Topics: Body Mass Index; Fats; Female; Humans; Lactose; Milk Proteins; Milk, Human
PubMed: 33675341
DOI: 10.1093/ajcn/nqaa410 -
Mayo Clinic Proceedings Dec 2019To determine the association of total and added fructose-containing sugars on cardiovascular (CVD) incidence and mortality. (Meta-Analysis)
Meta-Analysis
Relation of Total Sugars, Sucrose, Fructose, and Added Sugars With the Risk of Cardiovascular Disease: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies.
OBJECTIVE
To determine the association of total and added fructose-containing sugars on cardiovascular (CVD) incidence and mortality.
METHODS
MEDLINE, EMBASE and Cochrane Library were searched from January 1, 1980, to July 31, 2018. Prospective cohort studies assessing the association of reported intakes of total, sucrose, fructose and added sugars with CVD incidence and mortality in individuals free from disease at baseline were included. Risk estimates were pooled using the inverse variance method, and dose-response analysis was modeled.
RESULTS
Eligibility criteria were met by 24 prospective cohort comparisons (624,128 unique individuals; 11,856 CVD incidence cases and 12,224 CVD mortality cases). Total sugars, sucrose, and fructose were not associated with CVD incidence. Total sugars (risk ratio, 1.09 [95% confidence interval, 1.02 to 1.17]) and fructose (1.08 [1.01 to 1.15]) showed a harmful association for CVD mortality, there was no association for added sugars and a beneficial association for sucrose (0.94 [0.89 to 0.99]). Dose-response analyses showed a beneficial linear dose-response gradient for sucrose and nonlinear dose-response thresholds for harm for total sugars (133 grams, 26% energy), fructose (58 grams, 11% energy) and added sugars (65 grams, 13% energy) in relation to CVD mortality (P<.05). The certainty of the evidence using GRADE was very low for CVD incidence and low for CVD mortality for all sugar types.
CONCLUSION
Current evidence supports a threshold of harm for intakes of total sugars, added sugars, and fructose at higher exposures and lack of harm for sucrose independent of food form for CVD mortality. Further research of different food sources of sugars is needed to define better the relationship between sugars and CVD. REGISTRATION: clinicaltrials.gov, NCT01608620.
Topics: Cardiovascular Diseases; Fructose; Humans; Sucrose; Sugars; Sweetening Agents
PubMed: 31806098
DOI: 10.1016/j.mayocp.2019.05.034