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Frontiers in Public Health 2024Several pharmacological interventions, such as nicotine replacement therapy (NRT), varenicline, and bupropion, have been approved for clinical use of smoking cessation.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND AIMS
Several pharmacological interventions, such as nicotine replacement therapy (NRT), varenicline, and bupropion, have been approved for clinical use of smoking cessation. E-cigarettes (EC) are increasingly explored by many RCTs for their potentiality in smoking cessation. In addition, some RCTs are attempting to explore new drugs for smoking cessation, such as cytisine. This network meta-analysis (NMA) aims to investigate how these drugs and e-cigarettes compare regarding their efficacy and acceptability.
MATERIALS AND METHODS
This systematic review and NMA searched all clinical studies on smoking cessation using pharmacological monotherapies or e-cigarettes published from January 2011 to May 2022 using MEDLINE, COCHRANE Library, and PsychINFO databases. NRTs were divided into transdermal (TDN) and oronasal nicotine (ONN) by administrative routes, thus 7 network nodes were set up for direct and indirect comparison. Two different indicators measured the efficacy: prevalent and continuous smoking abstinence. The drop-out rates measured the acceptability.
RESULTS
The final 40 clinical studies included in this study comprised 77 study cohorts and 25,889 participants. Varenicline is more effective intervention to assist in smoking cessation during 16-32 weeks follow-up, and is very likely to prompt dropout. Cytisine shows more effectiveness in continuous smoking cessation but may also lead to dropout. E-cigarettes and oronasal nicotine are more effective than no treatment in encouraging prevalent abstinence, but least likely to prompt dropout. Finally, transdermal nicotine delivery is more effective than no treatment in continuous abstinence, with neither significant effect on prevalent abstinence nor dropout rate.
CONCLUSION
This review suggested and agreed that Varenicline, Cytisine and transdermal nicotine delivery, as smoking cessation intervention, have advantages and disadvantages. However, we had to have reservations about e-cigarettes as a way to quit smoking in adolescents.
Topics: Humans; Smoking Cessation; Electronic Nicotine Delivery Systems; Varenicline; Network Meta-Analysis; Tobacco Use Cessation Devices; Smoking Cessation Agents; Alkaloids; Azocines; Bupropion; Quinolizines; Nicotine; Quinolizidine Alkaloids
PubMed: 38841681
DOI: 10.3389/fpubh.2024.1361186 -
Drug Design, Development and Therapy 2024Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors... (Review)
Review
Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.
Topics: Humans; Hematologic Neoplasms; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic; Antineoplastic Agents; Models, Biological
PubMed: 38828021
DOI: 10.2147/DDDT.S458927 -
Dental Materials : Official Publication... Jun 2024Root canal irrigation endodontic solutions have effects on the chemistry of dentin. Infrared spectroscopy is a non-destructive chemical characterization method where the... (Review)
Review
BACKGROUND
Root canal irrigation endodontic solutions have effects on the chemistry of dentin. Infrared spectroscopy is a non-destructive chemical characterization method where the strength of absorption often correlates with mineral or organic composition.
OBJECTIVES
To survey effects of commonly used irrigation solutions on the composition of root dentin as detected by widely-available Fourier transform infrared spectroscopy (FTIR) methods.
METHODS
Electronic databases were searched for articles published between 1983 to 2023. After risk of bias assessments (OHAT), studies were grouped according to effects per irrigation solution. Inclusion criteria comprised in vitro studies that used extracted human or bovine teeth, treated by irrigation solutions characterized using FTIR spectroscopy and presenting spectral data. Publications that did not share FTIR spectra were excluded.
RESULTS
A wide range of concentrations, durations, and methodologies have been tested but only 30 out of 3452 studies met our inclusion criteria. Different FTIR methods were used with the Attenuated Total Reflection (ATR) variant being the most common (21 studies). Investigated solutions included sodium hypochlorite (NaOCl), ethylenediaminetetraacetic-acid (EDTA), 1-hydroxyethylidene-1-1-diphosphonic-acid (HEDP), peracetic-acid (PAA), glycolic-acid (GA), and citric-acid (CA) though most focused on NaOCl and EDTA. All solutions had detectable effects on the FTIR signature of dentin. NaOCl mainly affects the organic signatures, revealing reduced amide/phosphate ratios with increasing concentrations. EDTA mainly effects the inorganic component, increasing with time and concentration, yet glycolic acid has stronger effects than EDTA on dentin. Beyond the type of irrigant and dentin exposure durations, concentration and protocol of application had strong effects. There is a lack of studies comparing similar irrigants under conditions that mimic clinical scenarios analyzing bulk sample because FTIR of powder dentin differs from bulk measurements.
SIGNIFICANCE
The ideal root-canal irrigant should combine local disinfection properties with minimal compositional effects on healthy dentin. FTIR methods appear reliable to identify important changes in root dentin chemical composition. Such information can help understand when endodontic irrigation might lead to root degradation or possibly contribute to long term failures such as vertical fractures. Awareness of chemical damage from irrigation procedures may help clinicians select procedures that reduce deleterious effects on the root canal structures.
PubMed: 38825554
DOI: 10.1016/j.dental.2024.05.014 -
Phytomedicine : International Journal... Jul 2024Respiratory diseases pose a grave threat to human life. Therefore, understanding their pathogenesis and therapeutic strategy is important. Ferroptosis is a novel type of... (Review)
Review
BACKGROUND
Respiratory diseases pose a grave threat to human life. Therefore, understanding their pathogenesis and therapeutic strategy is important. Ferroptosis is a novel type of iron-dependent programmed cell death, distinct from apoptosis, necroptosis, and autophagy, characterised by iron, reactive oxygen species, and lipid peroxide accumulation, as well as glutathione (GSH) depletion and GSH peroxidase 4 (GPX4) inactivation. A close association between ferroptosis and the onset and progression of respiratory diseases, including chronic obstructive pulmonary disease, acute lung injury, bronchial asthma, pulmonary fibrosis, and lung cancer, has been reported. Recent studies have shown that traditional Chinese medicine (TCM) compounds exhibit unique advantages in the treatment of respiratory diseases owing to their natural properties and potential efficacy. These compounds can effectively regulate ferroptosis by modulating several key signalling pathways such as system Xc -GSH-GPX4, NCOA4-mediated ferritinophagy, Nrf2-GPX4, and Nrf2/HO-1, thus playing a positive role in improving respiratory diseases.
PURPOSE
This comprehensive review systematically outlines the regulatory role of ferroptosis in the onset and progression of respiratory diseases and provides evidence for treating respiratory diseases by targeting ferroptosis with TCM compounds. These insights aim to offer potential remedies for the clinical prevention and treatment of respiratory diseases.
STUDY DESIGN AND METHODS
We searched scientific databases PubMed, Web of Science, Scopus, and CNKI using keywords such as "ferroptosis","respiratory diseases","chronic obstructive pulmonary disease","bronchial asthma","acute lung injury","pulmonary fibrosis","lung cancer","traditional Chinese medicine","traditional Chinese medicine compound","monomer", and "natural product" to retrieve studies on the therapeutic potential of TCM compounds in ameliorating respiratory diseases by targeting ferroptosis. The retrieved data followed PRISMA criteria (preferred reporting items for systematic review).
RESULTS
TCM compounds possess unique advantages in treating respiratory diseases, stemming from their natural origins and proven clinical effectiveness. TCM compounds can exert therapeutic effects on respiratory diseases by regulating ferroptosis, which mainly involves modulation of pathways such as system Xc -GSH-GPX4,NCOA4-mediated ferritinophagy, Nrf2-GPX4, and Nrf2/HO-1.
CONCLUSION
TCM compounds have demonstrated promising potential in improving respiratory diseases through the regulation of ferroptosis. The identification of specific TCM-related inducers and inhibitors of ferroptosis holds great significance in developing more effective strategies. However, current research remains confined to animal and cellular studies, emphasizing the imperative for further verifications through high-quality clinical data.
Topics: Ferroptosis; Humans; Drugs, Chinese Herbal; Animals; Signal Transduction; Acute Lung Injury; Medicine, Chinese Traditional; Respiratory Tract Diseases; Reactive Oxygen Species; Pulmonary Fibrosis
PubMed: 38824825
DOI: 10.1016/j.phymed.2024.155738 -
Phytomedicine : International Journal... Jul 2024Sulforaphane (SFN) is a dietary isothiocyanate, derived from glucoraphanin, present in cruciferous vegetables belonging to the Brassica genus. It is a biologically... (Review)
Review
BACKGROUND
Sulforaphane (SFN) is a dietary isothiocyanate, derived from glucoraphanin, present in cruciferous vegetables belonging to the Brassica genus. It is a biologically active phytochemical that acts as a nuclear factor erythroid 2-related factor 2 (Nrf2) inducer. Thus, it has been reported to have multiple protective functions including anticancer responses and protection against a toxic agent's action.
PURPOSE
The present work systematically reviewed and synthesised the protective properties of sulforaphane against a toxic agent. This review reveals the mechanism of the action of SFN in each organ or system.
METHODS
The PRISMA guideline was followed in this sequence: researched literature, organised retrieved documents, abstracted relevant information, assessed study quality and bias, synthesised data, and prepared a comprehensive report. Searches were conducted on Science Direct and PubMed using the keywords "Sulforaphane" AND ("protective effects" OR "protection against").
RESULTS
Reports showed that liver and the nervous system are the target organs on which attention was focused, and this might be due to the key role of oxidative stress in liver and neurodegenerative diseases. However, protective activities have also been demonstrated in the lungs, heart, immune system, kidneys, and endocrine system. SFN exerts its protective effects by activating the Nrf2 pathway, which enhances antioxidant defenses and reduces oxidative stress. It also suppresses inflammation by decreasing interleukin production. Moreover, SFN inhibits apoptosis by preventing caspase 3 cleavage and increasing Bcl2 levels. Overall, SFN demonstrates multifaceted mechanisms to counteract the adverse effects of toxic agents.
CONCLUSION
SFN has potential clinical applications as a chemoprotective agent. Nevertheless, more studies are necessary to set the safe doses of SFN in humans.
Topics: Isothiocyanates; Sulfoxides; Humans; Animals; Brassica; Oxidative Stress; NF-E2-Related Factor 2; Protective Agents
PubMed: 38824824
DOI: 10.1016/j.phymed.2024.155731 -
Water Research Aug 2024Legionella is an opportunistic waterborne pathogen that causes Legionnaires' disease. It poses a significant public health risk, especially to vulnerable populations in...
Legionella is an opportunistic waterborne pathogen that causes Legionnaires' disease. It poses a significant public health risk, especially to vulnerable populations in health care facilities. It is ubiquitous in manufactured water systems and is transmitted via inhalation or aspiration of aerosols/water droplets generated from water fixtures (e.g., showers and hand basins). As such, the effective management of premise plumbing systems (building water systems) in health care facilities is essential for reducing the risk of Legionnaires' disease. Chemical disinfection is a commonly used control method and chlorine-based disinfectants, including chlorine, chloramine, and chlorine dioxide, have been used for over a century. However, the effectiveness of these disinfectants in premise plumbing systems is affected by various interconnected factors that can make it challenging to maintain effective disinfection. This systematic literature review identifies all studies that have examined the factors impacting the efficacy and decay of chlorine-based disinfectant within premise plumbing systems. A total of 117 field and laboratory-based studies were identified and included in this review. A total of 20 studies directly compared the effectiveness of the different chlorine-based disinfectants. The findings from these studies ranked the typical effectiveness as follows: chloramine > chlorine dioxide > chlorine. A total of 26 factors were identified across 117 studies as influencing the efficacy and decay of disinfectants in premise plumbing systems. These factors were sorted into categories of operational factors that are changed by the operation of water devices and fixtures (such as stagnation, temperature, water velocity), evolving factors which are changed in-directly (such as disinfectant concentration, Legionella disinfectant resistance, Legionella growth, season, biofilm and microbe, protozoa, nitrification, total organic carbon(TOC), pH, dissolved oxygen(DO), hardness, ammonia, and sediment and pipe deposit) and stable factors that are not often changed(such as disinfectant type, pipe material, pipe size, pipe age, water recirculating, softener, corrosion inhibitor, automatic sensor tap, building floor, and construction activity). A factor-effect map of each of these factors and whether they have a positive or negative association with disinfection efficacy against Legionella in premise plumbing systems is presented. It was also found that evaluating the effectiveness of chlorine disinfection as a water risk management strategy is further complicated by varying disinfection resistance of Legionella species and the form of Legionella (culturable/viable but non culturable, free living/biofilm associated, intracellular replication within amoeba hosts). Future research is needed that utilises sensors and other approaches to measure these key factors (such as pH, temperature, stagnation, water age and disinfection residual) in real time throughout premise plumbing systems. This information will support the development of improved models to predict disinfection within premise plumbing systems. The findings from this study will inform the use of chlorine-based disinfection within premise plumbing systems to reduce the risk of Legionnaires disease.
Topics: Disinfectants; Chlorine; Legionella; Disinfection; Chlorine Compounds; Water Microbiology; Chloramines; Water Supply; Oxides; Water Purification
PubMed: 38824796
DOI: 10.1016/j.watres.2024.121794 -
PloS One 2024The primary challenge encountered by individuals diagnosed with endometriosis is the experience of pain. Emerging research indicates that oxidative stress is implicated... (Meta-Analysis)
Meta-Analysis
Vitamin C and E antioxidant supplementation may significantly reduce pain symptoms in endometriosis: A systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
The primary challenge encountered by individuals diagnosed with endometriosis is the experience of pain. Emerging research indicates that oxidative stress is implicated in the initiation of pain associated with endometriosis. Vitamins C and E are known for their antioxidative properties. The primary objective of this study is to assess the efficacy of antioxidant supplementation, consisting of these vitamins, in the management of pain associated with endometriosis.
METHODS
A comprehensive search was conducted on the ClinicalTrials.gov, Scopus, Europe PMC, and Medline databases up until August 23rd, 2023, utilizing a combination of relevant keywords. This review incorporates literature that examines the relationship between antioxidant supplementation and pain in endometriosis. We employed fixed-effect models to analyze the risk ratio (RR) and present the outcomes together with their corresponding 95% confidence intervals (CI).
RESULTS
A total of five RCTs were incorporated. The results of our meta-analysis indicated that antioxidant supplementation with vitamin C and E combination was associated with higher proportion of endometriosis patients reporting reduced chronic pelvic pain (RR 7.30; 95%CI: 3.27-16.31, p<0.00001, I2 = 0%), alleviations of dysmenorrhea (RR 1.96; 95%CI: 1.25-3.07, p = 0.003, I2 = 39%), and dyspareunia (RR 5.08; 95%CI: 2.10-12.26, p = 0.0003, I2 = 0%) than patients only receiving placebo.
CONCLUSIONS
This study suggests the potential ability of vitamin C and E in alleviating pain symptoms experienced by individuals with endometriosis.
Topics: Female; Humans; Ascorbic Acid; Endometriosis; Antioxidants; Randomized Controlled Trials as Topic; Dietary Supplements; Vitamin E; Dysmenorrhea; Pelvic Pain; Dyspareunia
PubMed: 38820340
DOI: 10.1371/journal.pone.0301867 -
BMC Cardiovascular Disorders May 2024Despite their continued use, the effectiveness and safety of vasopressors in post-cardiac arrest patients remain controversial. This study examined the efficacy of... (Meta-Analysis)
Meta-Analysis
BACKGROUND & OBJECTIVE
Despite their continued use, the effectiveness and safety of vasopressors in post-cardiac arrest patients remain controversial. This study examined the efficacy of various vasopressors in cardiac arrest patients in terms of clinical, morbidity, and mortality outcomes.
METHODS
A comprehensive literature search was performed using online databases (MeSH terms: MEDLINE (Ovid), CENTRAL (Cochrane Library), Embase (Ovid), CINAHL, Scopus, and Google Scholar) from 1997 to 2023 for relevant English language studies. The primary outcomes of interest for this study included short-term survival leading to death, return of spontaneous circulation (ROSC), survival to hospital discharge, neurological outcomes, survival to hospital admission, myocardial infarction, and incidence of arrhythmias.
RESULTS
In this meta-analysis, 26 studies, including 16 RCTs and ten non-RCTs, were evaluated. The focus was on the efficacy of epinephrine, vasopressin, methylprednisolone, dopamine, and their combinations in medical emergencies. Epinephrine treatment was associated with better odds of survival to hospital discharge (OR = 1.52, 95%CI [1.20, 1.94]; p < 0.001) and achieving ROSC (OR = 3.60, 95% CI [3.45, 3.76], P < 0.00001)) over placebo but not in other outcomes of interest such as short-term survival/ death at 28-30 days, survival to hospital admission, or neurological function. In addition, our analysis indicates non-superiority of vasopressin or epinephrine vasopressin-plus-epinephrine therapy over epinephrine monotherapy except for survival to hospital admission where the combinatorial therapy was associated with better outcome (0.76, 95%CI [0.64, 0.92]; p = 0.004). Similarly, we noted the non-superiority of vasopressin-plus-methylprednisolone versus placebo. Finally, while higher odds of survival to hospital discharge (OR = 3.35, 95%CI [1.81, 6.2]; p < 0.001) and ROSC (OR = 2.87, 95%CI [1.97, 4.19]; p < 0.001) favoring placebo over VSE therapy were observed, the risk of lethal arrhythmia was not statistically significant. There was insufficient literature to assess the effects of dopamine versus other treatment modalities meta-analytically.
CONCLUSION
This meta-analysis indicated that only epinephrine yielded superior outcomes among vasopressors than placebo, albeit limited to survival to hospital discharge and ROSC. Additionally, we demonstrate the non-superiority of vasopressin over epinephrine, although vasopressin could not be compared to placebo due to the paucity of data. The addition of vasopressin to epinephrine treatment only improved survival to hospital admission.
Topics: Humans; Vasoconstrictor Agents; Treatment Outcome; Out-of-Hospital Cardiac Arrest; Risk Factors; Return of Spontaneous Circulation; Male; Middle Aged; Female; Aged; Time Factors; Cardiopulmonary Resuscitation; Epinephrine; Recovery of Function; Risk Assessment; Vasopressins; Patient Discharge; Adult
PubMed: 38816786
DOI: 10.1186/s12872-024-03962-4 -
BMC Anesthesiology May 2024Nasal surgeries, addressing anatomical variations for form and function, require careful anesthesia administration, including dexmedetomidine and remifentanil. This... (Meta-Analysis)
Meta-Analysis Comparative Study
BACKGROUND
Nasal surgeries, addressing anatomical variations for form and function, require careful anesthesia administration, including dexmedetomidine and remifentanil. This meta-analysis evaluates their safety and efficacy variations in nasal surgeries, emphasizing patient comfort and optimal outcomes.
METHODS
Four electronic databases (PubMed, Scopus, Web of Science, and CINAHL Complete) were searched for records in English. Studies that measure the effect of dexmedetomidine versus remifentanil on patients underwent nasal surgery were included. The Cochrane Collaboration's tool was used to assess the quality of the included studies. A random-effect model was preferred and statistical analysis was performed by Stata software version 17.
RESULTS
Out of an initial pool of 63 articles, five studies were selected for this analysis. All of these chosen studies were Randomized Controlled Trials (RCTs). The meta-analysis involved a total of 302 participants, with 152 in the remifentanil group and 150 in the dexmedetomidine group. The analysis aimed to compare the effects of Dexmedetomidine and Remifentanil on heart rate (HR) and mean arterial pressure (MAP) during surgery. Both groups exhibited similar MAP and HR, with the exception of a slightly lower HR in the remifentanil group at the 15th minute of surgery (Standardized Mean Difference: -0.24 [-0.83, 0.34]). Furthermore, when evaluating the impact of these medications on post-surgery outcomes, including pain levels, the use of pain relief medications, patient-surgeon satisfaction, agitation scores, and recovery time, no significant differences were observed between the two medications in any of these aspects.
CONCLUSION
In summary, the study compared Dexmedetomidine and Remifentanil in nasal surgeries anesthesia. No significant differences were found in heart rate, blood pressure, satisfaction, pain, agitation, or recovery time. The study had limitations, and future research should establish standardized protocols and consider various surgical factors.
Topics: Dexmedetomidine; Humans; Remifentanil; Nasal Surgical Procedures; Heart Rate; Randomized Controlled Trials as Topic; Hypnotics and Sedatives
PubMed: 38816731
DOI: 10.1186/s12871-024-02563-0 -
BMJ Open May 2024This systematic review with meta-analyses of randomised trials evaluated the preventive effects of vitamin A supplements versus placebo or no intervention on clinically... (Meta-Analysis)
Meta-Analysis
Effects of primary or secondary prevention with vitamin A supplementation on clinically important outcomes: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.
OBJECTIVES
This systematic review with meta-analyses of randomised trials evaluated the preventive effects of vitamin A supplements versus placebo or no intervention on clinically important outcomes, in people of any age.
METHODS
We searched different electronic databases and other resources for randomised clinical trials that had compared vitamin A supplements versus placebo or no intervention (last search 16 April 2024). We used Cochrane methodology. We used the random-effects model to calculate risk ratios (RRs), with 95% CIs. We analysed individually and cluster randomised trials separately. Our primary outcomes were mortality, adverse events and quality of life. We assessed risks of bias in the trials and used Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to assess the certainty of the evidence.
RESULTS
We included 120 randomised trials (1 671 672 participants); 105 trials allocated individuals and 15 allocated clusters. 92 trials included children (78 individually; 14 cluster randomised) and 28 adults (27 individually; 1 cluster randomised). 14/105 individually randomised trials (13%) and none of the cluster randomised trials were at overall low risk of bias. Vitamin A did not reduce mortality in individually randomised trials (RR 0.99, 95% CI 0.93 to 1.05; I=32%; p=0.19; 105 trials; moderate certainty), and this effect was not affected by the risk of bias. In individually randomised trials, vitamin A had no effect on mortality in children (RR 0.96, 95% CI 0.88 to 1.04; I=24%; p=0.28; 78 trials, 178 094 participants) nor in adults (RR 1.04, 95% CI 0.97 to 1.13; I=24%; p=0.27; 27 trials, 61 880 participants). Vitamin A reduced mortality in the cluster randomised trials (0.84, 95% CI 0.76 to 0.93; I=66%; p=0.0008; 15 trials, 14 in children and 1 in adults; 364 343 participants; very low certainty). No trial reported serious adverse events or quality of life. Vitamin A slightly increased bulging fontanelle of neonates and infants. We are uncertain whether vitamin A influences blindness under the conditions examined.
CONCLUSIONS
Based on moderate certainty of evidence, vitamin A had no effect on mortality in the individually randomised trials. Very low certainty evidence obtained from cluster randomised trials suggested a beneficial effect of vitamin A on mortality. If preventive vitamin A programmes are to be continued, supporting evidence should come from randomised trials allocating individuals and assessing patient-meaningful outcomes.
PROSPERO REGISTRATION NUMBER
CRD42018104347.
Topics: Humans; Vitamin A; Randomized Controlled Trials as Topic; Dietary Supplements; Primary Prevention; Secondary Prevention; Quality of Life; Vitamins
PubMed: 38816049
DOI: 10.1136/bmjopen-2023-078053