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Suthershinii G,1,* Weiling Amanda Tan,2,* Ainsley Ryan Yan Bin Lee,2 Matthew Zhixuan Chen3 1Department of Biological Sciences, National University of Singapore, Singapore, Singapore; 2Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 3Division of Geriatric Medicine, Department of Medicine, National University Hospital, Singapore*These authors contributed equally to this workCorrespondence: Matthew Zhixuan Chen, Division of Geriatric Medicine, Department of Medicine, National University Hospital, 1E Kent Ridge Road, Tower Block, Level 10 Department of Medicine, 119228, Singapore, Tel +65 6779 5555, Email zhixuan_matthew_chen@nuhs.edu.sgBackground: Chronic heart failure (CHF) is a debilitating condition that affects millions worldwide. It is accompanied by a myriad of adverse consequences, such asdiminishing of quality of life and deterioration of mental health. Caregivers play a pivotal role in helping CHF patients manage their conditions and symptoms, as a result the physical, mental and emotional state of caregivers have a direct impact on CHF patients and the management of this condition.Purpose: This systematic review aims to synthesize data about the effectiveness of behavioral interventions targeted at patients with chronic heart failure (CHF) and/or informal caregivers of CHF patients to improve overall management and treatment of CHF in the population.Patients and Methods: Three databases were searched for published studies and studies that included evaluated outcomes of interventions that targeted CHF patients or informal caregivers. All randomized controlled trials, trials of either experimental or quasi-experimental design were included. Studies that only involved formal caregivers, patient populations of adolescents/young adults and patients with non-chronic conditions were excluded.Results: Across the 21 included studies, no study reported a significant improvement in all three domains of quality of life (QoL), depression and loneliness of caregivers while only three studies reported a significant improvement in two outcomes. Within each domain, heterogeneity in measures limited quantitative pooling.Conclusion: This review provides data on the efficacy of interventions targeted at CHF patients and/or informal caregivers. It also highlights successful interventions and its features. Following this, additional resources need to be invested and directed towards implementing these interventions.Keywords: caregiver burden, chronic care, multidisciplinary care, psychosocial

Importance: Reliable estimates of the prevalence and risk of suicide and suicidal ideation (SI) among childhood cancer survivors (CCSs) are crucial in informing efforts to address this issue., Objective: To systematically evaluate the prevalence and risk of suicide and SI among CCSs., Data Sources: A literature search was conducted of PubMed, Embase, Cochrane Library, and PsycINFO from January 1, 2000, to November 17, 2024., Study Selection: All noncontrolled and controlled studies that evaluated the prevalence and risk of suicide and SI and drew comparisons between CCSs and their counterparts. Studies including participants older than 25 years, no reported outcomes, case studies, case reviews, and review articles were excluded., Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed with prospective PROSPERO registration. Prevalence was pooled for single-arm studies. Relative risk ratio (RR) was pooled for double-arm studies. Metaprop was used to meta-analyze the prevalence of suicide and SI under a generalized linear mixed model. For dichotomous outcomes, meta-analyses were performed to compute the RR of the psychological outcome compared with controls., Main Outcomes and Measures: Prevalence of suicide and SI, the RR of suicide and SI among CCSs compared with controls, and risk factors associated with suicidality outcomes., Results: From 531 records, 16 studies were included. Studies on suicide included 148 869 participants and studies on SI included 20 140 participants. The prevalence of suicide among CCSs was 0.30% (0.13%-0.69%) and of SI was 9% (95% CI, 7%-11%). There was a significantly increased risk of SI among CCSs compared with controls (RR, 1.67 [95% Cl, 1.39-2.01]), but not of suicide (RR, 1.50 [95% CI, 0.63-3.62]). Subgroup analyses suggested that prevalence of SI is much higher during the active cancer period than years after (proportion, 0.14 [95% CI, 0.10-0.19] vs 0.08 [95% CI, 0.06-0.09]). The systematic review identified preexisting mental illness, poor physical health, older age, male sex, and being single as risk factors associated with suicidality outcomes., Conclusions and Relevance: In this meta-analysis of suicide and SI among CCSs, the risk of suicide was no different among CCSs compared with controls, but CCSs had a higher risk of SI. Future studies are needed to explore suicidality outcomes among CCSs to guide targeted support policies.

Importance: Cancer and its treatment negatively impact the mental health of older adults. The potential of exercise interventions as a complementary treatment to alleviate the psychological impacts of cancer is promising, but there are gaps in the current literature., Objective: To determine if exercise interventions are associated with improvements in psychological outcomes among older adults with cancer., Data Sources: PubMed, Embase, PsycINFO, and Cochrane databases were searched from database inception to November 5, 2024. Search terms used were geriatrics, cancer, depression, anxiety, quality of life, and exercise interventions., Study Selection: English-language randomized clinical trials (RCTs) that analyzed the association of various exercise interventions with at least 1 of 3 psychological outcomes (depression, anxiety, or health-related quality-of-life [HRQOL]) were included. The control groups were given usual care. Studies were included if the mean age of participants was older than 60 years and had participants with a diagnosis of any cancer regardless of comorbidities., Data Extraction and Synthesis: Studies were screened, and data were extracted by 2 independent authors. Random-effects meta-analyses and meta-regressions were used for analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed., Main Outcomes and Measures: The primary outcomes were depression, anxiety, and HRQOL. Standardized mean difference (SMD) was used to quantify the association of exercise interventions with outcomes., Results: A total of 27 RCTs with 1929 participants were included. Meta-analyses observed an association of exercise with a significant reduction in levels of depression (SMD = -0.53; 95% CI, -0.79 to -0.28) and anxiety (SMD = -0.39; 95% CI, -0.66 to -0.12) and improvements in overall HRQOL (SMD = 0.63; 95% CI, 0.10 to 1.17). Subgroup analyses revealed that mind-body exercise interventions were significantly associated with improved depression (SMD = -0.89; 95% CI, -1.51 to -0.27) and anxiety levels (SMD = -0.77; 95% CI, -1.54 to -0.01) compared with conventional exercise interventions., Conclusion: In this systematic review and meta-analysis of 27 RCTs, exercise interventions were found to be associated with significantly reduced levels of depression and anxiety and significantly improved HRQOL in older adults with cancer. These findings suggest that health care professionals and policymakers should focus more on implementing exercise interventions to improve mental health outcomes in this vulnerable population.

Purpose: Cancer therapies including trastuzumab and anthracyclines are cardiotoxic and cause cardiac dysfunction. To prevent cardiotoxicity, pharmacological agents used in heart failure have been administered concomitantly with cardiotoxic cancer therapy, but few studies to date have performed a head-to-head comparison of these different agents. This systematic review and network meta-analysis of randomized-controlled trials aims to evaluate the efficacy of renin-angiotensin-aldosterone system (RAAS) blockers, namely angiotensin-converting enzyme inhibitors (ACE-Is), aldosterone receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), in primary prevention against chemotherapy-related cardiac dysfunction in patients receiving anthracyclines and/or trastuzumab., Methods: A systematic search was performed in major web databases for studies from inception to 15 September 2022. A Bayesian network meta-analysis model was used to assess the relative effects of competing treatments on the primary outcomes of risk of significant decline in left ventricular ejection fraction (LVEF) and mean LVEF decline. Secondary outcomes included left ventricular diastolic function, global longitudinal strain, and cardiac biomarkers. This study is registered with PROSPERO, CRD42022357980., Results and Conclusion: Nineteen studies reported the effects of 13 interventions (N = 1905 patients). Only enalapril (RR 0.05, 95% CI 0.00-0.20) was associated with reduced risk of patients developing significant decline in LVEF relative to placebo. Subgroup analysis showed that the beneficial effect of enalapril was driven by protection against anthracycline-associated toxicity. In addition, no RAAS-inhibiting agents showed efficacy in protection against treatment with both anthracycline and trastuzumab. The use of RAAS inhibition therapy did not conclusively impact on other markers of cardiac function, including left ventricular diastolic function and cardiac biomarkers., Competing Interests: Declarations. Ethics Approval and Consent to Participate: Not applicable, as no human and animal subjects or data were used. Consent for Publication: Not applicable. Competing Interests: The authors have no relevant financial or non-financial interests to disclose., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Autoimmune diseases pose significant health challenges worldwide and affect millions. In recent years, there has been growing interest in exploring preventive strategies through nutritional interventions using vitamins, antioxidants, and micronutrients to reduce the risk of developing autoimmune diseases. However, excessive supplementation has also been associated with toxicity., Objective: We aim to assess how the intake of vitamins, antioxidants and micronutrients affect the risk of developing autoimmune diseases., Methods: This PRISMA-adherent systematic review involved a systematic search of PubMed, Embase and Cochrane for controlled studies that evaluated the risk of incident autoimmune diseases after supplementation. Random effects meta-analyses were used for primary analysis., Results: 18 studies were included. Overall meta-analyses observed that vitamin D did not influence the risk of autoimmune diseases (RR=0.99, 95%CI: 0.81-1.20). However, among the different vitamin D dosages, subgroup analysis demonstrated that those who were supplemented with 600-800IU/day may have a statistically significant reduction in risk (RR=0.55, 95%CI: 0.38; 0.82). Systematic review suggested that consumption of most vitamins, micronutrients and antioxidants may not have any effect on the risk of autoimmune diseases. Smoking, age, physical or outdoor activity and diet were significant confounding factors that affected the efficacy of such interventions., Conclusion: We studied the effect of various vitamins, micronutrients and antioxidants on the risk of developing autoimmune diseases. Our study contributes to the evolving landscape of nutritional immunology, providing a foundation for future research to unravel more definite relationships with supplementation and the development of incident autoimmune diseases., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024504796., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Low, Loke, Chew, Lee and Tay.)

Background: Various studies have highlighted the increased incidence and symptoms of depression and anxiety in paediatric cancer survivors (PCS). Yet no meta-analysis has focused on post-traumatic stress disorder (PTSD) or post-traumatic stress symptoms (PTSS) in PCS and their family nucleus., Aims: To evaluate the overall risk of PTSD and severity of PTSS in PCS and their family nucleus. Secondary objectives include identifying potential risk factors of PTSD and high PTSS., Method: We systematically searched PubMed, Embase and PsycINFO for studies comparing the risk of PTSD and PTSS severity among PCS, their family nucleus and non-cancer controls. PRISMA reporting guidelines were followed. Random effects meta-analyses and meta-regressions were conducted., Results: From 1089 records, we included 21 studies. PCS have an increased risk of PTSD (risk ratio 2.36, 95% CI 1.37-4.06) and decreased PTSS severity (standardised mean difference -0.29, 95% CI -0.50 to -0.08). Subgroup analyses of other categorical study-level characteristics revealed that female PCS who were older at diagnosis and data collection had a significantly higher risk of PTSD. Meta-regression were insignificant. Family nucleus did not show a significantly increased risk of PTSD (risk ratio 1.13, 95% CI 0.59-5.00) and PTSS severity (standardised mean difference 0.53, 95% CI -0.00 to 1.06). Systematically reviewing studies on the family nucleus found that the majority reported a significantly increased risk of psychological trauma compared with the comparator. Lower education, income and social status were also risk factors., Conclusions: Timely identification and interventions are imperative for policy makers and healthcare providers to prevent trauma from worsening in this population group.

Introduction: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416)., Methods: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m 2 every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures., Results: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased., Conclusions: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Social media use has grown in importance and prevalence, with its estimated number of users at 4.9 billion worldwide. Social media use research has revealed positive and negative impacts on users' mental health and well-being. However, such impacts among adults have not been examined in any reviews., Methods: A scoping review was conducted based on the framework by Arksey and O'Malley and reported based on the PRISMA-ScR guidelines. Eight databases were searched from 2005 to December 2021. Articles were included after being reviewed by three independent teams, with discrepancies resolved through consensus with the senior author. Publication-related information (i.e., authors, year of publication, aims, study population, methodology, interventions, comparisons, outcome measures and key findings) were extracted from each study. Thematic analysis was conducted to answer the research questions., Results: Among the 114 eligible articles, young adults (69.6%) represented the main age group. Most studies (78.6%) focused on the negative impacts of social media use on mental health and well-being, with nearly a third (32.1%) assessing such impacts on depression. Notably, this scoping review found that more than three-quarters (78.6%) of the included studies revealed that excessive and passive social media use would increases depression, anxiety, mood and loneliness. Nevertheless, a third (33.0%) also reported positive impacts, where positive and purposeful use of social media contributes to improvements in mental health and well-being, such as increased perceived social support and enjoyment., Linking Evidence to Action: This review has provided an overview of the existing knowledge on how social media use affects adults and identified areas of research that merit investigation in future studies. More attention should be given to maximizing the positive impacts of social media use on mental health and well-being among adults., (© 2024 Sigma Theta Tau International.)

Context: Diabetes mellitus is associated with morbid complications such as diabetic foot ulcers (DFUs) that may lead to amputations or mortality if not managed adequately., Objective: New adjunctive interventions to treat diabetic wounds include topical biologics and growth factors. This study aims to evaluate their efficacy in improving wound-healing outcomes and safety., Methods: Comprehensive database searches of MEDLINE via PubMed, EMBASE, and Cochrane were performed from inception to December 2022. Three independent researchers selected the studies. Randomized controlled trials that compared the use of a topical biologic growth factor-containing regimen to other biologics or standard of care (SOC) were included. This review followed PRISMA guidelines. Risk of bias analysis was performed using the Jadad scale. Network meta-analysis was performed. Treatments were grouped into common nodes based on the type of biologic agent. Primary outcomes of interest were healing rate and time to wound closure. Secondary outcomes included wound infection, serious adverse events (AEs), and amputation rate., Results: Human umbilical cord (HUC) was associated with the highest cure, followed by recombinant human epidermal growth factor (hEGF). A significantly greater reduction in the time to cure DFUs was seen in HUC, hEGF, and fibroblast growth factor (FGF). There was a significantly lower risk of AEs when platelet-rich plasma (PRP) was administered., Conclusion: HUC, hEGF, and FGF are promising topical biologics with statistically significant primary outcomes compared to SOC, while PRP is effective in reducing ulcer-related AEs. HUC has been found to be the most effective in terms of cure rate and a reduction in time to cure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: The incidence and mortality of cancer is increasing worldwide with studies reporting that cumulative risk of cancer rises as age increases. Against the backdrop of the increasing prevalence of cancer amongst older patients, we conducted a systematic review and meta-analysis examining the depression-mortality relationship in older adults with cancer (OAC)., Materials and Methods: This PRISMA-adherent systematic review involved a systematic search of PubMed, Medline, EMBASE, and PsycINFO for prospective and retrospective cohort studies comparing the risk of all-cause and cancer-related mortality among OAC with depression. Random effects meta-analyses and meta-regressions were used for the primary analysis., Results: From 5,280 citations, we included 14 cohort studies. Meta-analyses of hazard ratios (HRs) showed an increased incidence of all-cause mortality in OAC with depression (pooled HR: 1.40; 95% confidence interval [CI]: 1.25, 1.55). Subgroup analyses of other categorical study-level characteristics were insignificant. While risk of cancer-related mortality in OAC with depression was insignificantly increased with a pooled HR of 1.21 (95% CI: 0.98, 1.49), subgroup analysis indicated that risk of cancer-related mortality in OAC with depression significantly differed with cancer type. Our systematic review found that having fewer comorbidities, a higher education level, greater socioeconomic status, and positive social supportive factors lowered risk of all-cause mortality in OAC with depression., Discussion: Depression in OAC significantly increases risk of all-cause mortality and cancer-related mortality among different cancer types. It is imperative for healthcare providers and policy makers to recognize vulnerable subgroups among older adults with cancer to individualize interventions., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any personal, commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Recent trials suggest glucagon-like peptide-1 receptor agonists (GLP-1RAs) may have a cardioprotective role by reducing major adverse cardiac events, stroke mortality and heart failure-related hospitalisations. We examined whether and how GLP-1RAs affect cardiac function in cardiovascular and metabolic diseases including type 2 diabetes, heart failure and post-myocardial infarction., Methods: In this PRISMA-adherent systematic review and meta-analysis, three databases were searched from inception to July 2021 and registered on PROSPERO (CRD42021259661)., Results: 20 reports of 19 randomized placebo-controlled trials including 2062 participants were meta-analyzed. Among type 2 diabetes patients, GLP-1RA resulted in improved systolic function measured by circumferential strain (mean difference [MD]= -5.48; 95% CI: -10.47 to -0.49; P= 0.03; I 2 = 89%) and diastolic dysfunction measured by E / A (MD= -0.15; 95% CI: -0.25 to -0.05; P= 0.003; I 2 = 0%). For post-myocardial infarction patients, GLP-1RA reduced infarct size (g) (MD= -5.36; 95% CI: -10.68 to -0.04; P= 0.05; I 2 = 78%). Liraglutide, but not exenatide, demonstrated improved systolic function, by increasing left ventricular ejection fraction (MD= 4.89; 95% CI: 3.62 to 6.16; P< 0.00001; I 2 = 0%) and reducing left ventricular end-systolic volume (MD= -4.15; 95% CI: -7.49 to -0.81; P = 0.01; I 2 = 0%). Among heart failure patients, no significant changes were noted., Conclusion: GLP-1RA drugs may improve systolic and diastolic function in type 2 diabetes and reduce infarct size post-acute myocardial infarction with no demonstrable effect on cardiac function in heart failure. Tailored recommendations for the use of GLP-1RAs for cardioprotection should be considered for each patient's condition., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Patients with systemic lupus erythematosus (SLE) have increased risk of premature atherosclerosis but the exact mechanisms remains unclear. Flow-mediated dilatation (FMD) is an established non-invasive assessment of vascular endothelial function. Lipoprotein subfractions may be better predictors of FMD than conventional cholesterol measurements. We tested the hypothesis that lipoprotein subfractions are independently associated with FMD., Methods: Forty-one consecutive adult patients with SLE without known cardiovascular risk factors or disease were recruited in this cross-sectional study. Endothelial function and early atherosclerosis were assessed by brachial FMD and common carotid artery (CCA) intima-media thickness (IMT). High-density lipoprotein (HDL)/low-density lipoprotein (LDL) subfractions were measured. Machine learning models were also constructed to predict FMD and CCA IMT., Results: Median FMD was 4.48% (IQR 5.00%) while median IMT was 0.54 mm (IQR 0.12 mm). Univariate analysis showed lower LDL1 (r=-0.313, p<0.05) and higher HDL2 subfractions (r=0.313, p<0.05) were significantly associated with higher log-transformed FMD. In a multiple linear regression model, HDL2 (β=0.024, SE=0.012, p<0.05) remained an independent predictor of higher FMD after adjusting for age, body mass index, LDL1 and systolic blood pressure. The machine learning model included parameters such as HDL2 (positive association), prednisolone dose, LDL cholesterol and LDL1 for prediction of FMD (r=0.433, p<0.01). Age, LDL cholesterol and systolic blood pressure were independently associated with higher CCA IMT after adjusting for body mass index and HDL2., Conclusions: HDL 2, a large HDL particle, was independently associated with greater FMD and may be a biomarker of vascular health in SLE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Suicide risk may be increased in patients with Parkinson disease (PD), a common neurodegenerative condition. Mood disorders, especially depression, are prevalent in patients with PD who report suicidality., Objective: To address inconsistent results from studies of suicidal ideation and behavior in patients with PD., Data Sources: The study team searched MEDLINE and Embase from inception to June 14, 2023, and further screened the bibliographies of relevant studies to ensure a comprehensive search., Study Selection: Original studies, published in English, discussing either suicidal ideation, behavior, or both in adults with PD were included. Accepted study designs included cross-sectional, case-control, and cohort studies. Studies that only included patients with PD after deep brain stimulation were excluded., Data Extraction and Synthesis: This meta-analysis was conducted in line with the PRISMA guidelines. Two authors reviewed each study and extracted the data independently, with discrepancies referred to a third independent author., Main Outcomes and Measures: Outcomes included the prevalence of suicidal ideation and behavior, measured as proportions, and the risk of suicidal behavior in patients with PD relative to controls, measured in both odds ratio (OR) and hazards ratio (HR)., Results: A total of 28 studies comprising 505 950 PD patients were included in the final analysis. The prevalence of suicidal ideation was evaluated in 14 studies (22.2%; 95% CI, 14.6-32.3) and suicidal behavior in 21 studies (1.25%; 95% CI, 0.64-2.41). Excluding 4 outliers, prevalence of suicidal behavior was significantly higher in prospective studies (1.75%; 95% CI, 1.03-2.95) than retrospective studies (0.50%; 95% CI, 0.24-1.01). Excluding 1 outlier, OR of suicidal behavior was pooled across 10 studies and significant (OR, 2.15; 95% CI, 1.22-3.78; P = .01). HR of suicidal behavior was assessed in 9 studies (HR, 1.73; 95% CI, 1.40-2.14; P < .001)., Conclusions and Relevance: This meta-analysis involving more than 500 000 patients with PD found 22.2% and 1.25% of patients with PD to have suicidal ideation and behavior, respectively. Patients with PD had 2 times the risk of suicidal behavior than controls. Early recognition and management of suicidality in PD can help reduce mortality.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. Low molecular weight heparin (LMWH) has been the standard of care but new guidelines have approved the use of non-vitamin K antagonist oral anticoagulants (NOAC). By conducting an individual patient data (IPD) meta-analysis of randomised controlled trials (RCTs) comparing the outcomes of NOAC versus LMWH in cancer patients, we aim to determine an ideal strategy for the prophylaxis of VTE and prevention of VTE recurrence. Three databases were searched from inception until 19 October 2022. IPD was reconstructed from Kaplan-Meier curves. Shared frailty, stratified Cox and Royston-Parmar models were fit to compare the outcomes of venous thromboembolism recurrence and major bleeding. For studies without Kaplan-Meier curves, aggregate data meta-analysis was conducted using random-effects models. Eleven RCTs involving 4844 patients were included. Aggregate data meta-analysis showed that administering NOACs led to a significantly lower risk of recurrent VTE (RR = 0.65; 95%CI: 0.50-0.84) and deep vein thrombosis (DVT) (RR = 0.60; 95%CI: 0.40-0.90). In the IPD meta-analysis, NOAC when compared with LMWH has an HR of 0.65 (95%CI: 0.49-0.86) for VTE recurrence. Stratified Cox and Royston-Parmar models demonstrated similar results. In reducing risks of recurrent VTE and DVT among cancer patients, NOACs are superior to LMWHs without increased major bleeding.

Background and Aims: Nonsmall cell lung cancer accounts for over 85% of lung cancer incidences worldwide, and often has a poor prognosis. Proteasome inhibitors, such as bortezomib, have previously demonstrated evidence in preclinical and clinical models in the treatment of NSCLC both alone and as part of chemotherapeutic regimens., Methods: Five databases were searched from inception to February 2023 to identify published clinical trial data and ongoing clinical trials on the use of proteasome inhibitors in treatment of NSCLC with a comprehensive search strategy., Results: This review examines the clinical evidence from 21 completed and published phase I and II trials studying the use of bortezomib monotherapy and combination therapy in the treatment of NSCLC. Bortezomib/docetaxel combination resulted in longer median time-to-progression (TTP), median duration of response, median duration of disease control and median progression-free survival (PFS) than bortezomib monotherapy, with concurrent administration having greater 6-month PFS and median overall survival (OS) than sequential administration. Bortezomib/vorinostat with chemotherapy was well tolerated and effective. Bortezomib/gemcitabine/carboplatin, bortezomib/bevacizumab/carboplatin and bortezomib/paclitaxel/carboplatin combinations showed promising results and were of further investigational value., Conclusion: Bortezomib showed some clinical promise in combination therapy but not monotherapy. It also demonstrated a manageable side effect profile. Combination regimens are of further investigation value in Phase II trials., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Importance: Despite patients with cancer being at risk of poor outcomes from COVID-19, there are few published studies for vaccine efficacy in this group, with suboptimal immunogenicity and waning vaccine efficacy described in small studies being a concern., Objective: To assess the incidence rate of severe COVID-19 disease outcomes associated with the number of vaccine doses received and the waning of protection over time., Design, Setting, and Participants: A prospective multicenter observational cohort study was carried out over 2 time periods (September 15, 2021, to December 20, 2021 [delta wave], and January 20, 2022, to November 11, 2022 [omicron wave]) predominated by SARS-CoV-2 delta and omicron variants, respectively. Overall, 73 608 patients with cancer (23 217 active treatment, 50 391 cancer survivors) and 621 475 controls matched by age, sex, race and ethnicity, and socioeconomic status were included., Exposure: Vaccine doses received, from zero to 4 doses, and time elapsed since last vaccine dose., Outcomes: Competing-risk regression analyses were employed to account for competing risks of death in patients with cancer. Main outcomes were incidence rate ratios (IRRs) of COVID-19 infection, hospitalization, and severe disease (defined as requirement for supplemental oxygen, intensive care, or death). The IRRs stratified by time from last vaccine dose served as indicators of waning of vaccine effectiveness over time., Results: The mean (SD) age of actively treated patients with cancer, cancer survivors, and controls were 62.7 (14.7), 62.9 (12.6), and 61.8 (14.7) years, respectively. Of 73 608 patients with cancer, 27 170 (36.9%) were men; 60 100 (81.6%) were Chinese, 7432 (10.1%) Malay, 4597 (6.2%) Indian, and 1479 (2.0%) were of other races and ethnicities. The IRRs for the 3-dose and 4-dose vs the 2-dose group (reference) for COVID-19 hospitalization and severe disease were significantly lower during both the delta and omicron waves in cancer and control populations. The IRRs for severe disease in the 3-dose group for active treatment, cancer survivors, and controls were 0.14, 0.13, and 0.07 during the delta wave and 0.29, 0.19, and 0.21 during omicron wave, respectively. The IRRs for severe disease in the 4-dose group during the omicron wave were even lower at 0.13, 0.10 and 0.10, respectively. No waning of vaccine effectiveness against hospitalization and severe disease was seen beyond 5 months after a third dose, nor up to 5 months (the end of this study's follow-up) after a fourth dose., Conclusion: This cohort study provides evidence of the clinical effectiveness of mRNA-based vaccines against COVID-19 in patients with cancer. Longevity of immunity in preventing severe COVID-19 outcomes in actively treated patients with cancer, cancer survivors, and matched controls was observed at least 5 months after the third or fourth dose.

Importance: A cancer diagnosis and treatment may result in highly traumatic periods with lasting psychological consequences for children, adolescent, and young adult patients with cancer (CYACs). Early identification and management may prevent long-term psychological morbidity and suicide., Objective: To analyze risk, severity, and risk factors for depression, anxiety, psychotic disorders, and suicide in CYACs and noncancer comparators., Data Sources: Literature search of PubMed, MEDLINE, Embase, PsycINFO, CINAHL, and PubMed Central from January 1, 2000, to November 18, 2022., Study Selection: Full-length articles in peer-reviewed journals that measured and reported risk and/or severity of depression, anxiety, psychotic disorders, and suicide mortality in CYACs and a noncancer comparator group., Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed with prospective PROSPERO registration., Main Outcomes and Measures: Risk ratios (RRs) were used for dichotomous outcomes, and standardized mean differences (SMDs) were used for continuous outcomes. SMDs were defined as follows: 0.2, small; 0.5, medium; and 0.8, large. Sources of heterogeneity and risk factors were investigated using sensitivity, subgroup, and meta-regression analyses., Results: From 7319 records, 52 studies were included. Meta-analyses revealed that CYACs were at increased lifetime risk of severe symptoms or a disorder of depression (RR, 1.57; 95% CI, 1.29-1.92), anxiety (RR, 1.29; 95% CI, 1.14-1.47), and psychotic disorders (RR, 1.56; 95% CI, 1.36-1.80) relative to both matched controls and their siblings. Overall suicide mortality was not significantly elevated (RR, 1.63; 95% CI, 0.78-3.40). The mean severity of depression was found to be elevated in CYACs receiving treatment (SMD, 0.44; 95% CI, 0.13-0.74) and long-term survivors (SMD, 0.18; 95% CI, 0.02-0.33). The mean severity of anxiety was found to be elevated only during treatment (SMD, 0.16; 95% CI, 0.03-0.20)., Conclusions and Relevance: Findings of this systematic review and meta-analysis suggest that CYACs may experience lasting psychological burden long into survivorship. Timely identification, preventive efforts, and psycho-oncological intervention for psychological comorbidity are recommended.

Objective: To systematically evaluate the risk factors of depression and anxiety in older adults with cancer., Method: This PRISMA-adherent systematic review (PROSPERO CRD42022372747) involved a systematic database search for prospective and retrospective cohort studies., Results: We included 33 cohort studies with 31 evaluating depression and seven evaluating anxiety. Systematic synthesis yielded various protective and exacerbating factors for depression and anxiety amongst older adults with cancer. These factors span a range of domains: (1) Cancer and associated treatment-related factors; (2) Medical, physical and functional factors; (3) Demographic factors and; (4) Social and lifestyle factors. At the individual-level, the most significant factors were the presence of chronic medical comorbidities, having pre-existing psychological symptoms, and poor baseline physical and functional status. Within the social unit, the degree of social support and presence of a partner were most significant., Conclusion: The deleterious impact comorbid psychological symptoms can have on older adults with cancer can be profound. In this review, we highlight a range of protective and exacerbating factors identified from cohort studies that may enable policymakers to tailor and individualise interventions to manage depression, anxiety and associated burden in this vulnerable population. The relative paucity of studies evaluating anxiety highlights an important research gap., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: A diagnosis of cancer and treatment may constitute a highly traumatic period for paediatric cancer patients (PYACPs). However, no review has comprehensively analysed how the mental health of PYACPs is acutely affected and the longitudinal course., Methods: This systematic review followed PRISMA guidelines. Comprehensive searches of databases were conducted to identify studies of depression, anxiety and post-traumatic stress symptoms in PYACPs. Random effects meta-analyses were used for the primary analysis., Results: From 4898 records, 13 studies were included. Acutely after diagnosis, depressive and anxiety symptoms were significantly elevated in PYACPs. Depressive symptoms only significantly decreased after 12 months (standardised mean difference, SMD = -0.88; 95% CI: -0.92, -0.84). This downward trajectory persisted to 18 months (SMD = -1.862; 95% CI: -1.29, -1.09). Anxiety symptoms similarly only decreased after 12 (SMD = -0.34; 95% CI: -0.42, -0.27) up to 18 months (SMD = -0.49; 95% CI: -0.60, -0.39) after the cancer diagnosis. Post-traumatic stress symptoms showed protracted elevations throughout follow-up. Overall, significant predictors of poorer psychological outcomes included unhealthy family functioning, concomitant depression or anxiety, poor cancer prognosis or experiencing cancer and treatment-related side effects., Conclusions: While depression and anxiety may improve over time with a favourable environment, post-traumatic stress may have a protracted course. Timely identification and psycho-oncological intervention are critical.

Background: Anthracyclines form the backbone of many systemic chemotherapy regimens but are accompanied by dose-limiting cardiotoxicity. We elucidate the progression and severity of cardiac function over time, in the absence of cardioprotection, which less is known about., Methods: This PRISMA-guideline-adherent review was registered on PROSPERO (CRD42022373496)., Results: 26 studies met the eligibility criteria including a total of 910 patients. The overall reduction in post-anthracycline pooled mean left ventricular ejection fraction (LVEF) in placebo arms of the included randomised-controlled trials was 4.5% (95% CI, 2.6 to 6.4). The trend in LVEF showed a progressive decline until approximately 180 days, after which there was no significant change. Those receiving a cumulative anthracycline dose of 300 mg/m2 experienced a more profound reduction. The overall pooled risk of a 10% absolute decline in LVEF from baseline, or a decline to an LVEF below 50%, was 17% (95% CI: 11 to 24; I2 = 71%). Sensitivity analyses of baseline LVEF and trastuzumab treatment status did not yield significant differences., Conclusion: While the mean LVEF decline in patients without cardioprotective therapy was clinically small, a vulnerable subset experienced significant impairment. Further research to best identify those who benefit most from cardioprotective therapies when receiving anthracyclines is required.

Introduction: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity., Method: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases., Results: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P <0.05) and chemotherapy (92.8%±18.1, P <0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection., Conclusion: This study demonstrates the benefit of early administration of the third dose among cancer patients.

Background: Transcranial alternating current stimulation (TACS) is a non-invasive method of brain stimulation that is hypothesised to alter cortical excitability and brain electrical activity, modulating functional connectivity within the brain. Several trials have demonstrated its potential in treating psychiatric disorders such as depression and schizophrenia., Objectives: To study the efficacy of TACS in ameliorating symptoms of depression and schizophrenia in patients and its effects on cognition in patients and healthy subjects compared to sham stimulation., Design: Systematic review with meta-analysis., Data Sources and Methods: This PROSPERO-registered systematic review (CRD42022331149) is reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, EMBASE, CENTRAL and PsycINFO were searched from inception to March 2022. Only randomised-controlled trials were included., Results: A total of 12 randomised-controlled trials are reviewed for meta-analysis, with three randomised-controlled trials reporting only effects on cognition in psychiatric and cognitively impaired patients, three trials on cognition in healthy subjects, one trial on cognition in both patients and healthy subjects, one trial on only depression, two on both cognition and depression in patients and two on schizophrenia symptoms. No studies were at significant risk of bias. For cognition, TACS showed significant improvement [positive standardised mean differences (SMD) denoting improvement] over sham stimulation in those with psychiatric disorders with an SMD of 0.60 (95% confidence interval [CI]: 0.14, 1.06). Similarly, among patients with depression, an SMD of 1.14 (95% CI: 0.10, 2.18) was found significantly favouring TACS over sham stimulation. Two studies assessed the effect of TACS on schizophrenia symptoms with mixed results., Conclusion: TACS has shown promise in ameliorating symptoms of both schizophrenia and depression in patients. TACS also improves cognition in both patients and healthy subjects. However, these findings are limited by the sample size of included studies, and future studies may be required to better our understanding of the potential of TACS., Registration: PROSPERO (CRD42022331149)., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Importance: Patients with cancer have an increased risk of severe disease and mortality from COVID-19, as the disease and antineoplastic therapy cause reduced vaccine immunogenicity. Booster doses have been proposed to enhance protection, and efficacy data are emerging from several studies., Objective: To evaluate the proportion of COVID-19 primary vaccination non-responders with cancer who seroconvert after a booster dose., Methods: PubMed, EMBASE, CENTRAL and medRxiv were searched from 1st January 2021 to 10th March 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal checklist., Results: After the eligibility assessment, 22 studies were included in this systematic review and 17 for meta-analysis of seroconversion in non-responders, pooling a total of 849 patients with haematological cancer and 82 patients with solid cancer. Haematological cancer non-responders exhibited lower seroconversion at 44% (95% CI 36-53%) than solid cancer at 80% (95% CI 69-87%). Individual patient data meta-analysis found the odds of having a meaningful rise in antibody titres to be significantly associated with increased duration between the second and third dose (OR 1.02, 95% CI 1.00-1.03, P ≤ 0.05), age of patient (OR 0.960, 95% CI 0.934-0.987, P ≤ 0.05) and cancer type. With patients with haematological cancer as a reference, patients with lung cancer had 16.8 times the odds of achieving a meaningful increase in antibody titres (OR 16.8, 95% CI 2.95-318, P ≤ 0.05) and gastrointestinal cancer patients had 25.4 times the odds of achieving a meaningful increase in antibody titres (OR 25.4, 95% CI 5.26-492.21, P ≤ 0.05)., Conclusions: administration of a COVID-19 vaccine booster dose is effective in improving seroconversion and antibody levels. Patients with haematological cancer consistently demonstrate poorer response to booster vaccines than patients with solid cancer., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YYS—honoraria (AstraZeneca); RS—honoraria (MSD, Eli Lilly, BMS, Roche, Taiho, Astra Zeneca, DKSH), consulting or advisory role (Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, MSD, GSK), research funding (Paxman Coolers, MSD), travel (Roche, Astra Zeneca, Taiho, Eisai, DKSH). DB—Sana Biotechnology has licensed intellectual property of DB and Washington University in St. Louis. Gilead Biosciences has licensed intellectual property of D.B. and Stanford University. DB is a co-founder of Clade Therapeutics. DB serves on a COVID-19 therapeutics advisory panel for GlaxoSmithKline. BJL—has a financial interest in Cofactor Genomics, Inc. and Iron Horse Dx. RTS—receives research funding from Merck, Rafael Pharmaceuticals, ImmunoVaccine, Bayer, SeaGen, Exelixis, Pieris, LOXO Oncology, Novocure, NuCana, QED and has served as a consultant/advisor to Merck, Servier, Astra-Zeneca, EMD Serono, Taiho, QED, Incyte, Genentech, Basilea. YH—Honoraria from ABBVIE, Janssen, Astra-Zeneca, Roche and Medison, all outside of the submitted work. All other authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Diabetes is a leading chronic illness in the modern world and 19-34% develop chronic diabetic foot ulcers (DFUs) in their lifetime, often necessitating amputation. The reduction in tissue growth factors and resulting imbalance between proteolytic enzymes and their inhibitors, along with systemic factors impairing healing appear particularly important in chronic wounds. Growth factors applied topically have thus been suggested to be a non-invasive, safe, and cost-effective adjunct to improve wound healing and prevent complications. Comprehensive database searches of MEDLINE via PubMed, EMBASE, Cochrane, and ClinicalTrials.gov were performed to identify clinical evidence and ongoing trials. The risk of bias analysis included randomized controlled trials (RCTs) was performed using the Cochrane Risk of Bias 2.0 tool. We included randomized controlled trials that compared the use of a topical biologic growth factor-containing regimen to any other regimen. Primary outcomes of interest were time to wound closure, healing rate, and time. Secondary outcomes included the incidence of adverse events such as infection. A total of 41 trials from 1992-2020 were included in this review, with a total recorded 3,112 patients. Platelet-derived growth factors (PDGF) in the form of becaplermin gel are likely to reduce the time of closure, increase the incidence of wound closure, and complete wound healing. Human umbilical cord-related treatments, dehydrated human amnion and chorion allograft (dHACA), and hypothermically stored amniotic membrane (HSAM), consistently increased the rates and incidence of complete ulcer healing while reducing ulcer size and time to complete ulcer healing. Fibroblast growth factor-1 (FGF1) showed only a slight benefit in multiple studies regarding increasing complete ulcer healing rates and incidence while reducing ulcer size and time to complete ulcer healing, with a few studies showing no statistical difference from placebo. Platelet-rich fibrin (PRF) is consistent in reducing the time to complete ulcer healing and increasing wound healing rate but may not reduce ulcer size or increase the incidence of complete ulcer healing. Targeting the wound healing pathway via the extrinsic administration of growth factors is a promising option to augment wound healing in diabetic patients. Growth factors have also shown promise in specific subgroups of patients who are at risk of significantly impaired wound healing such as those with a history of secondary infection and vasculopathy. As diabetes impairs multiple stages of wound healing, combining growth factors in diabetic wound care may prove to be an area of interest. Evidence from this systematic literature review suggests that topical adjuncts probably reduce time to wound closure, reduce healing time, and increase the healing rate in patients with chronic DFUs., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Wong et al.)

Introduction: Colorectal cancer screening when done early can significantly reduce mortality. However, screening compliance is still lower than expected even in countries with established screening programs. Motivational interviewing is an approach that has been explored to promote behavioral change including screening compliance. This review synthesizes the efficacy of motivational interviewing in promoting uptake of colorectal screening modalities and is the only review so far that examines motivational interviewing for colorectal cancer screening alone., Methods: A systematic review and meta-analysis was conducted to examine the effects of motivational interviewing for colorectal cancer screening. PubMed, EMBASE, CENTRAL, PsycINFO, and CINAHL were searched to identify eligible studies from inception to June 2021 and selection criteria was defined. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. The DerSimonian and Laird random effects model was used in the statistical analysis for studies included in the meta-analysis., Results: Fourteen studies from 14 randomized-controlled trials with a low to moderate risk of bias were analyzed. 8 studies in the systematic review showed that motivational interviewing is superior to a control group. Meta-analysis was conducted on 11 studies and showed that motivational interviewing is statistically significant in increasing colorectal cancer screening rates in both intention-to-treat and per-protocol analysis. Timing of data collection of colorectal cancer screening rates did not make a significant difference to the efficacy of motivational interviewing. Studies that offered and accepted a mixture of colorectal screening modalities such as colonoscopy and fecal immunochemical tests were significantly more likely to have favorable colorectal screening outcomes. Heterogeneity in intervention was noted between studies, specifically differences in the training of interventionists, intervention delivery and comparator components., Conclusion: Motivational interviewing is a tailored intervention demonstrating mixed evidence in improving colorectal cancer screening attendance amongst individuals. More research is needed to rigorously compare the effect of motivational interviewing alone vs. in combination with other screening promotion strategies to enhance colorectal cancer screening compliance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Long, Lau, Lee, Yam, Koh and Ho.)

Background: Seroconversion and longevity of vaccine-induced immune response is blunted in immune-mediated inflammatory disease (IMID) patients owing to immunosuppressive regimens. COVID-19 booster vaccines after a primary series have been proposed with inconclusive evidence on efficacy to date., Methods: This PROSPERO-registered systematic review (CRD42022302534) was conducted according to PRISMA guidelines. PubMed, EMBASE, CENTRAL, Web of Science, CORD-19, WHO ICTRP, and medRxiv were searched up to 28 February 2022 for eligible studies. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tools., Results: From 6647 records, 17 prospective studies were included for systematic review and 12 in meta-analysis of primary series non-responders. The risk of bias was low. Pooling 340 non-responders, a booster dose proved effective with 0.47 seroconverting (95% CI: 0.32-0.63, I2 = 82%). Rituximab therapy was associated with significant impairment, with risks of 0.25 (95% CI: 0.17-0.36, I2 = 50.7%) versus 0.81 (95% CI: 0.72-0.87, I2 = 0.0%) for those without rituximab therapy. A systematic review of antibody levels against COVID-19 showed several-fold increases across studies. Incidence of local and systemic adverse events, including disease flares, were either comparable or slightly increased after the booster dose compared to primary series. No major events such as myocarditis or death were reported., Conclusion: Our results show that booster doses are effective in eliciting seroconversion in non-responders, bolstering immunity to COVID-19. It has also not been associated with major adverse events.

Background: Recently, it has been discovered that anti-inflammatory and anti-oxidative pathways play a role in depression and anxiety. Lower serum levels of antioxidants, such as vitamin E, have been implicated in both depression and anxiety., Methods: This PROSPERO-registered systematic review (Reference: CRD42021260058) is reported according to PRISMA guidelines. PubMed, EMBASE, CENTRAL, PsycINFO, and CINAHL were searched from inception to June 2021., Results: Twelve studies were included in this systematic review, and nine in meta-analysis of vitamin E versus placebo. For depression, meta-analysis of 354 participants showed a standardised mean difference of -0.88 (95% CI: -1.54, -0.21; I2 = 87%) favouring vitamin E. For anxiety, meta-analysis of 306 participants showed a standardised mean difference of -0.86 (95% CI: -2.11, 0.40; I2 = 95%) favouring vitamin E. Three of the studies involved a pure comparison of vitamin E against placebo, while others included constituents such as omega-3 fatty acids. Nine of the studies were at low risk of bias, two had some concerns, and one was at high risk of bias., Conclusion: Vitamin E supplementation has shown inconclusive results in ameliorating both depression and anxiety. Containing a reassuring safety profile and low cost, future studies would be of promise, and they would benefit from both larger sample sizes and from excluding other constituents, such as omega-3 fatty acids, from experimental and comparator arms.