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Vitamin C and scar strength: analysis of a historical trial and implications for collagen-related pathologies.
Hujoel, PP, Hujoel, MLA
The American journal of clinical nutrition. 2022;(1):8-17
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Abstract
A double-blind controlled trial initiated in 1944 has led to the common narrative that a 10-mg daily vitamin C intake is adequate to prevent and treat impaired wound healing, and by inference, other collagen-related diseases such as heart disease or stroke. The WHO relies on this narrative to set the recommended nutrient intake for vitamin C. This narrative, however, is based on what is known as the eyeball method of data assessment. The 1944 trial published individual participant data on scar strength providing an opportunity to statistically probe the validity of the 10-mg narrative, something which has not yet been done. The findings show that a vitamin C intake that averages to 10 mg/d over a mean follow-up of 11.5 mo was associated with a 42% weakened scar strength when compared with 80 mg vitamin C intake/d (P < 0.001). The observed dose-response curve between scar strength and vitamin C intake suggests that the daily vitamin C intake needed to prevent collagen-related pathologies is in the range recommended by the National Academy of Medicine and the European Food Safety Authority (75 to 110 mg/d), not the WHO recommendation (45 mg/d). The findings also show that a vitamin C intake that averages to 65 mg/d over a mean follow-up of 6.5 mo failed to restore the normal wound-healing capacity of vitamin C-depleted tissues; such tissues had a 49% weaker scar strength when compared with nondepleted tissues (P < 0.05). Thus, average daily vitamin C intakes ∼50% higher than the WHO recommends may fail to treat existing collagen-related pathologies. It is concluded that the prior lack of statistical analyses of a landmark trial may have led to a misleading narrative on the vitamin C needs for the prevention and treatment of collagen-related pathologies.
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Randomized controlled trial to test the efficacy of a brief, communication-based, substance use preventive intervention for parents of adolescents: Protocol for the SUPPER Project (Substance Use Prevention Promoted by Eating family meals Regularly).
Skeer, MR, Sabelli, RA, Rancaño, KM, Lee-Bravatti, M, Ryan, EC, Eliasziw, M, Spirito, A
PloS one. 2022;(2):e0263016
Abstract
BACKGROUND Substance use among adolescents in the U.S. is associated with adverse physical and mental health outcomes in the long-term. Universal youth-focused substance use prevention programs have demonstrated effectiveness but are often not sustainable due to the significant amount of time, effort, and resources required. We describe a trial protocol for a brief, low-participant-burden intervention to improve substance use-specific parent-child communication through the promotion of family meals and increased parental engagement. METHODS This study is a parallel-group randomized controlled trial designed to assess the efficacy of a 13-week intervention. A total of 500 dyads of parents and their 5th-7th grade children are recruited from across Massachusetts. Dyads are randomized to the intervention or attention-control condition using block urn randomization, based on child grade, gender, and school. Parents/guardians in the substance use preventive intervention arm receive a short handbook, attend two meetings with an interventionist, and receive two SMS messages per week. Parents/guardians in the control arm receive the same dose but with content focused on nutrition, physical activity, and weight stigma. Participant dyads submit videos of family meals, audio recordings of prompted conversations, and quantitative surveys over an 18-month period (baseline, 3, 6, 12, 18 months post-intervention). The primary outcomes measure the quantity and quality of parent-child substance use conversations and proximal child indicators (i.e., substance use attitudes and expectancies, affiliation with substance-using peers, and intentions and willingness to use substances). The secondary outcome is child substance use initiation. DISCUSSION This is a novel, brief, communication-focused intervention for parents/guardians that was designed to reduce participant burden. The intervention has the potential to improve parent-child engagement and communication and conversations about substance use specifically and decrease child substance use risk factors and substance use initiation. TRIAL REGISTRATION ClinicalTrials.gov NCT03925220. Registered on 24 April 2019.
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The Effect of L-Carnitine on Mortality Rate in Septic Patients: A Systematic Review and Meta-Analysis on Randomized Clinical Trials.
Abdollahi, H, Abdolahi, M, Sedighiyan, M, Jafarieh, A
Endocrine, metabolic & immune disorders drug targets. 2021;(4):673-681
Abstract
BACKGROUND Recent clinical trial studies have reported that L-carnitine supplementation can reduce the mortality rate in patients with sepsis, but there are no definitive results in this context. The current systematic review and meta-analysis aimed to evaluate the effect of L-carnitine supplementation on 28-day and one-year mortality in septic patients. METHODS A systematic search conducted on Pubmed, Scopus and Cochrane Library databases up to June 2019 without any language restriction. The publications were reviewed based on the Cochrane handbook and preferred reporting items for systematic reviews and meta-analyses (PRISMA). To compare the effects of L-carnitine with placebo, Risk Ratio (RR) with 95% confidence intervals (CI) were pooled according to the random effects model. RESULTS Across five enrolled clinical trials, we found that L-carnitine supplementation reduce one-year mortality in septic patients with SOFA> 12 (RR: 0.68; 95% CI: 0.49 to 0.96; P= 0.03) but had no significant effect on reducing 28-day mortality ((RR: 0.93; 95% CI: 0.68 to 1.28; P= 0.65) compared to placebo. Finally, we observed that based on current trials, L-carnitine supplementation may not have clinically a significant effect on mortality rate. CONCLUSION L-carnitine patients with higher SOFA score can reduce the mortality rate. However, the number of trials, study duration and using a dosage of L-carnitine are limited in this context and further large prospective trials are required to clarify the effect of L-carnitine on mortality rate in septic patients.
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Adenoma and Advanced Adenoma Detection Rates of Water Exchange, Endocuff, and Cap Colonoscopy: A Network Meta-Analysis with Pooled Data of Randomized Controlled Trials.
Shao, PP, Bui, A, Romero, T, Jia, H, Leung, FW
Digestive diseases and sciences. 2021;(4):1175-1188
Abstract
BACKGROUND AND AIMS A network meta-analysis showed that low-cost optimization of existing resources was as effective as distal add-on devices in increasing adenoma detection rate (ADR). We assessed the impacts of water exchange (WE), Endocuff, and cap colonoscopy on ADR and advanced adenoma detection rate (AADR). We hypothesized that WE may be superior at improving ADR and AADR. METHODS The literature was searched for all randomized controlled trials (RCTs) that reported ADR as an outcome and included the keywords colonoscopy, and water exchange, Endocuff, or cap. We performed traditional network meta-analyses with random effect models comparing ADR and AADR of each method using air insufflation (AI) as the control and reported the odds ratios with 95% confidence interval. Performances were ranked based on P-score. RESULTS Twenty-one RCTs met inclusion criteria. Fourteen RCTs also reported AADR. Both WE [1.46 (1.20-1.76)] and Endocuff [1.39 (1.17-1.66)] significantly increase ADR, while cap has no impact on ADR [1.00 (0.82-1.22)]. P-scores for WE (0.88), Endocuff (0.79), cap (0.17), and AI (0.17) suggest WE has the highest ADR. WE [1.38 (1.12-1.70)], but not Endocuff [0.96 (0.76-1.21)] or cap [1.06 (0.85-1.32)], significantly increases AADR. P-scores for WE (0.98), cap (0.50), AI (0.31), and Endocuff (0.21) suggest WE is more effective at increasing AADR. The results did not change after adjusting for age, proportion of males, and withdrawal time. CONCLUSION WE may be the modality of choice to maximally improve ADR and AADR.
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Effect of saffron supplementation on liver enzymes: A systematic review and meta-analysis of randomized controlled trials.
Hasani, M, Malekahmadi, M, Rezamand, G, Estêvão, MD, Pizarro, AB, Heydari, H, Hoong, WC, Arafah, OA, Barakeh, ARR, Rahman, A, et al
Diabetes & metabolic syndrome. 2021;(6):102311
Abstract
BACKGROUND AND AIMS Possible protective effects of saffron (Crocus sativus L) have been reported in several randomized clinical trials (RCTs). Current systematic review was performed to summarize the efficacy of saffron intake on liver enzymes. METHODS An electronic database search was conducted on PubMed/Medline, Scopus, Web of Science, and Cochrane for RCTs comparing effect of saffron and placebo on liver enzymes from inception to July 2021. There was no restriction in language of included studies and we calculated the standardized mean difference (SMD) and 95% Confidence Intervals (CI) for each variable. Random-effect model was used to calculate effect size. RESULTS Eight studies (n = 463 participants) were included in the systematic review. The saffron intake was associated with a statistically significant decrease in aspartate aminotransferase (AST) (SMD: -0.18; 95% CI: -0.34, -0.02; I2 = 0%) in comparison to placebo intake. Our results also indicated that saffron consumption did not have a significant effect on alanine aminotransferase (ALT) (SMD: -0.14; 95% CI: -0.36, 0.09; I2 = 47.0%) and alkaline phosphatase (ALP) levels (SMD: 0.14; 95% CI: -0.18, 0.46; I2 = 42.9%) compared to placebo. CONCLUSIONS Saffron intake showed beneficial impacts on circulating AST levels. However, larger well-designed RCTs are still needed to clarify the effect of saffron intake on these and other liver enzymes.
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Hiding unhealthy heart outcomes in a low-fat diet trial: the Women's Health Initiative Randomized Controlled Dietary Modification Trial finds that postmenopausal women with established coronary heart disease were at increased risk of an adverse outcome if they consumed a low-fat 'heart-healthy' diet.
Noakes, TD
Open heart. 2021;(2)
Abstract
The Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHIRCDMT) was designed to test whether the US Department of Agriculture's 1977 Dietary Guidelines for Americans protects against coronary heart disease (CHD) and other chronic diseases. The only significant finding in the original 2006 WHIRCDMT publication was that postmenopausal women with CHD randomised to a low-fat 'heart-healthy' diet in 1993 were at 26% greater risk of developing additional CHD events compared with women with CHD eating the control diet. A 2017 WHIRCDMT publication includes data for an additional 5 years of follow-up. It finds that CHD risk in this subgroup of postmenopausal women had increased further to 47%-61%. The authors present three post-hoc rationalisations to explain why this finding is 'inadmissible': (1) only women in this subgroup were less likely to adhere to the prescribed dietary intervention; (2) their failure to follow the intervention diet increased their CHD risk; and (3) only these women were more likely to not have received cholesterol-lowering drugs. These rationalisations appear spurious. Rather these findings are better explained as a direct consequence of postmenopausal women with features of insulin resistance (IR) eating a low-fat high-carbohydrate diet for 13 years. All the worst clinical features of IR, including type 2 diabetes mellitus (T2DM) in some, can be 'reversed' by the prescription of a high-fat low-carbohydrate diet. The Women's Health Study has recently reported that T2DM (10.71-fold increased risk) and other markers of IR including metabolic syndrome (6.09-fold increased risk) were the most powerful predictors of future CHD development in women; blood low-density lipoprotein-cholesterol concentration was a poor predictor (1.38-fold increased risk). These studies challenge the prescription of the low-fat high-carbohydrate heart-healthy diet, at least in postmenopausal women with IR, especially T2DM. According to the medical principle of 'first do no harm', this practice is now shown to be not evidence-based, making it scientifically unjustifiable, perhaps unethical.
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Prevention of Urinary Stones With Hydration (PUSH): Design and Rationale of a Clinical Trial.
Scales, CD, Desai, AC, Harper, JD, Lai, HH, Maalouf, NM, Reese, PP, Tasian, GE, Al-Khalidi, HR, Kirkali, Z, Wessells, H, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(6):898-906.e1
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Abstract
RATIONALE & OBJECTIVE Although maintaining high fluid intake is an effective low-risk intervention for the secondary prevention of urinary stone disease, many patients with stones do not increase their fluid intake. STUDY DESIGN We describe the rationale and design of the Prevention of Urinary Stones With Hydration (PUSH) Study, a randomized trial of a multicomponent behavioral intervention program to increase and maintain high fluid intake. Participants are randomly assigned (1:1 ratio) to the intervention or control arm. The target sample size is 1,642 participants. SETTING & PARTICIPANTS Adults and adolescents 12 years and older with a symptomatic stone history and low urine volume are eligible. Exclusion criteria include infectious or monogenic causes of urinary stone disease and comorbid conditions precluding increased fluid intake. INTERVENTIONS All participants receive usual care and a smart water bottle with smartphone application. Participants in the intervention arm receive a fluid intake prescription and an adaptive program of behavioral interventions, including financial incentives, structured problem solving, and other automated adherence interventions. Control arm participants receive guideline-based fluid instructions. OUTCOMES The primary end point is recurrence of a symptomatic stone during 24 months of follow-up. Secondary end points include changes in radiographic stone burden, 24-hour urine output, and urinary symptoms. LIMITATIONS Periodic 24-hour urine volumes may not fully reflect daily behavior. CONCLUSIONS With its highly novel features, the PUSH Study will address an important health care problem. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION Registered at ClinicalTrials.gov with study number NCT03244189.
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The effect of N-acetylcysteine on bipolar depression: a systematic review and meta-analysis of randomized controlled trials.
Pittas, S, Theodoridis, X, Haidich, AB, Bozikas, PV, Papazisis, G
Psychopharmacology. 2021;(7):1729-1736
Abstract
RATIONALE The current pharmacotherapy of bipolar depression often presents limited efficacy and increased risk for adverse events. N-acetylcysteine (NAC) has been suggested as potentially effective and well-tolerated adjunctive treatment for bipolar disorder (BD). OBJECTIVES This systematic review and meta-analysis aimed to examine the efficacy of N-acetylcysteine, as an adjunctive therapy, for treating bipolar depression. METHODS PubMed, Cochrane Library, Scopus databases, and grey literature were searched for studies retrieval. Randomized controlled trials including patients with a diagnosed bipolar disorder and a current depressive episode were included in the analysis. The measured variables included symptoms, functioning, and quality of life scales. The mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) was set as the primary outcome. RESULTS A total of five studies were included in the analysis. A significant improvement was not observed from the addition of NAC to standard therapy in symptomatology [MADRS (MD = -3.32; 95% CI = -12.79 to 6.16), Young Mania Rating Scale (MD = -0.7; 95% CI = -2.15 to 0.75), Bipolar Depression Rating Scale (MD = -3.19; 95% CI = -15.48 to 9.1), and Clinical Global Impression for severity (MD = -0.13; 95% CI = -0.33 to 0.08)], functioning, [Global Assessment of Functioning Scale (MD = 3.21; 95% CI = -12.55 to 18.97), Social and Occupational Functioning Assessment Scale (MD = 0.47; 95% CI = -4.60 to 5.53), or quality of life [Quality of Life Enjoyment and Satisfaction Questionnaire (MD = 2.27; 95% CI = -9.13 to 13.67)]. CONCLUSIONS There is no evidence indicating that NAC has beneficial effects as an adjunctive treatment for bipolar depression. Future trials with improved methodological design and efficient sample sizes are required to draw safer conclusions.
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Designing Clinical Trials in Wilson's Disease.
Ott, P, Ala, A, Askari, FK, Czlonkowska, A, Hilgers, RD, Poujois, A, Roberts, EA, Sandahl, TD, Weiss, KH, Ferenci, P, et al
Hepatology (Baltimore, Md.). 2021;(6):3460-3471
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Abstract
BACKGROUND AND AIMS Wilson's disease (WD) is an autosomal-recessive disorder caused by ATP7B gene mutations leading to pathological accumulation of copper in the liver and brain. Adoption of initial treatments for WD was based on empirical observations. These therapies are effective, but there are still unmet needs for which treatment modalities are being developed. An increase of therapeutical trials is anticipated. APPROACH AND RESULTS The first Wilson Disease Aarhus Symposium (May 2019) included a workshop on randomized clinical trial design. The authors of the article were organizers or presented during this workshop, and this article presents their consensus on the design of clinical trials for WD, addressing trial population, treatment comparators, inclusion and exclusion criteria, and treatment endpoints. To achieve adequate recruitment of patients with this rare disorder, the study groups should include all clinical phenotypes and treatment-experienced as well as treatment-naïve patients. CONCLUSIONS The primary study endpoint should be clinical or a composite endpoint until appropriate surrogate endpoints are validated. Standardization of clinical trials will permit pooling of data and allow for better treatment comparisons, as well as reduce the future numbers of patients needed per trial.
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Impact of COVID-19 on Prevention of Urinary Stones with Hydration (PUSH) Study: Challenges and Opportunities for Future Trials.
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The Journal of urology. 2021;(3):502-504