Supplementation Arm Research Articles

Does Vitamin D3 Supplementation Improve Depression Scores among Rural Adolescents? A Randomized Controlled Trial.

Contemporary evidence has been established demonstrating that stunted vitamin D levels are associated with depression, poor mood, and other mental disorders. Individuals with normal vitamin D levels have a much lower probability of developing depression. Improving vitamin D levels by supplementation has shown betterment in depressive patients among different age groups. The objective of this study was to assess the effect of vitamin D supplementation on depression scores among rural adolescents. This study was a cluster randomized controlled trial carried out for a period of 3 years among adolescents from rural Kolar. The sample size was calculated based on previous research and was determined to be 150 for each group. The intervention arm received 2250 IU of vitamin D, and the control arm received a lower dose of 250 IU of vitamin D for 9 weeks. To assess sociodemographic status, a pretested, semi-structured questionnaire was used, and, to assess depression, the Beck Depression Inventory (BDI-II) was used. A baseline assessment was carried out for vitamin D status and depression status, followed by a post-intervention assessment. From the start of the trial, the participants were contacted every week by the pediatric team to investigate any side effects. Out of 235 school students in the vitamin D supplementation arm, 129 (54.9%) belonged to the 15 years age group, 124 (52.8%) were boys, and 187 (79.6%) belonged to a nuclear family. Out of 216 school students in the calcium supplementation arm, 143 (66.2%) belonged to the 15 years age group, 116 (53.7%) were girls, and 136 (63%) belonged to a nuclear family. By comparing Beck depression scores before and after the intervention, it was found that the vitamin D intervention arm showed a statistically significant reduction in Beck depression scores. The present study showed that vitamin D supplementation reduced depression scores, showing some evidence that nutritional interventions for mental health issues such as depression are an excellent option. Vitamin D supplementation in schools can have numerous beneficiary effects on health while mutually benefiting mental health.

Magnesium supplementation therapy to prevent cisplatin-induced acute nephrotoxicity in pediatric cancer: a randomized phase-2 trial.

The present study aimed to examine the effect of magnesium (Mg) supplementation on cisplatin-induced nephrotoxicity (CIN) in pediatric cancer patients. The present phase-2, open-label, multicenter, randomized controlled trial enrolled patients aged less than 20years who were scheduled to receive cisplatin-containing chemotherapy and randomly allocated them at a ratio of 1:1 to a Mg supplementation arm with even-numbered chemotherapy courses (arm AB) or another arm with odd-numbered courses (arm BA). Analysis objects were reconstructed into two groups depending on whether the chemotherapy course had Mg supplementation (group B) or not (group A). The primary outcome was the proportion of chemotherapy courses resulting in elevated serum creatinine per chemotherapy course. The secondary outcomes included efficacies evaluated using other biomarkers and the safety of the Mg supplementation. Twenty-eight patients were randomly allocated to either group (16 to arm AB and 12 to arm BA). The baseline characteristics of the groups were similar. There was no significant difference in the proportion of courses with increased serum creatinine between the groups (group A: 10% vs. group B: 6%; P = 0.465) nor was any significant difference observed in other biomarkers during any chemotherapy course. The Mg value during chemotherapy was significantly higher in group B than that in group A. No adverse events related to magnesium administration were observed. The study design, which treated a single chemotherapy course as a study object, failed to detect a statistically significant benefit of Mg supplementation for preventing CIN in pediatric cancer patients. JRCT ( https://jrct.niph.go.jp/ ) Identifier UMIN000029215 jRCTs031180251. UMIN-CTR ( http://www.umin.ac.jp/icdr/index.html ) Identifier UMIN000029215.

Impact of Iron Supplementation in Anemic Voluntary First-Time Blood Donors-Results of a Pilot Trial in Ghana

Introduction : Blood transfusion is a major developmental challenge in sub-Saharan Africa due to chronic inadequacy and shortage of major blood products. In Ghana, deferral of potential blood donors has been identified as a significant challenge. Anemia, accounts for nearly half of ineligible blood donors. The estimated prevalence of anemia is 42.4% in women of reproductive age and 18.8% among peri-urban men ( Spring and Ghana Health service 2016). Thus, a high prevalence of anemia accounting for nearly half of voluntary blood donor deferrals, may contribute to the country's poor availability of safe blood for transfusion. No prior investigation had been carried out in Ghana on whether potential blood donors, deferred due to anemia, would consider donating blood after receiving counselling and appropriate treatment. This study tested the hypothesis that low-dose iron supplementation will increase hemoglobin levels sufficiently among anemic individuals to make them eligible to donate blood. Data from this trial informed the design of a larger randomized control type 1 pragmatic effectiveness implementation hybrid trial. Methods:This was a longitudinal two-arm parallel-group trial (participants aged 18 - 60 years). We compared the hemoglobin levels among those with anemia, iron deficiency (ID) or iron deficiency anemia (IDA) who received iron supplementation to donors without ID or IDA (Control group) in a non-inferiority design(NCT04949165). Anemia, IDA and ID were defined and determined using World Health Organization cut-off values (WHO, 2011). Potential blood donors with hemoglobin values less than 10 g/dl were excluded from the study. Participants in the iron supplementation arm were given low-dose iron (65 mg elemental iron) three times weekly for four months while the control arm received the standard nutritional counselling practice. In-person visits occurred at two, four and six months and included blood draws for full blood count, peripheral blood film smear, malaria rapid test and serum ferritin. The primary outcome was hemoglobin level after four months. A structured questionnaire assessed adherence, nutritional counselling and adverse events every two weeks via phone. Results: Two hundred and twenty-three first-time voluntary blood donors consented and passed pre-screening donation requirements (105 in iron supplementation arm vs. 118 in the control arm). The mean ages were similar between the iron supplementation and control groups (19.7±2.5 vs. 20.1±3.1 years). In both groups, there were more females than males (iron: 75.2%; control: 51.7%). At screening, 43.9% (98/223) had anemia while 3.1% (7/223) had ID. Of those who had anemia, 84.7% (83/98) had ferritin at least 15 g/l while 15.3% (15/98) had IDA. Among controls who donated blood at screening with an interim 1 visit, 42.6% (20/47) of females and 20.9% (9/43) of males were anemic. Only 23.4% (11/47) of females but no male was ID after one blood donation. Among participants assigned to iron supplementation who were anemic at screening, 31.7% (20/63) of females and 28.6% (6/21) of males were no longer anemic at interim visit 1. Among iron participants who were ID at screening 53.3% (8/15) of females and no male (0/2) were iron replete at interim visit 1. Only half of the participants receiving iron supplementation self-reported perfect adherence at the first and second interim visits (end of iron supplementation). A small proportion of participants reported side effects of dark stools and abdominal pain. We did not observe bacterial infections or increased malaria incidence. The mean hemoglobin values decreased over time from baseline to month four in the control group (screening: N=118, 13.4±1.3 g/dl; interim visit 2: N=74, 12.3±1.5 g/dl) and increased in the iron supplementation group (screening: N=105, 11.3±0.9 g/dl; interim visit 2: N=56, 11.4±1.3 g/dl). However, the primary comparison, mean hemoglobin difference between the iron supplementation and control arm at four months, did not meet the threshold to reject the inferiority hypothesis. Conclusion: The prevalence of ID and IDA among voluntary first-time blood donors was lower than previously published estimates. Adherence to low-dose iron supplementation three times a week was poor. Hemoglobin levels in the iron supplementation arm were not close enough to those in the control group after four months of iron supplementation to declare non-inferiority.

Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial

The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy. RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588. Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31-40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per μL (IQR 145-316) and median HIV-1 RNA was 5·2 log10 copies per mL (4·6-5·7). At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]). Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis. Wellcome Trust.

The Impact of Baseline 25-Hydroxyvitamin D Level and Gestational Age on Prenatal Vitamin D Supplementation to Prevent Offspring Asthma or Recurrent Wheezing

BackgroundPrenatal vitamin D deficiency is associated with asthma or recurrent wheezing in offspring. However, evidence from randomized trials on the efficacy of vitamin D supplementation is inconclusive. ObjectivesWe aimed to examine the differential efficacy of prenatal vitamin D supplementation based on the maternal baseline vitamin D status and the starting time of supplementation to prevent early life asthma or recurrent wheezing. MethodsWe conducted a secondary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized double-blind trial of prenatal vitamin D supplementation initiated at 10–18 weeks (wks) of gestation (4400 IU of intervention/day compared with 400 IU of placebo/day) to prevent offspring asthma or recurrent wheezing by the age of 6 years. We assessed the effect of modification of supplementation by maternal baseline vitamin D status at enrollment and the timing of initiation of supplementation. ResultsAn inverse relationship was observed between maternal 25-hydroxyvitamin D (25(OH)D) levels at trial entry and 25(OH)D levels during late pregnancy (32–38 wks of gestation) in both supplementation arms (P < 0.001). Overall, supplementation efficacy was not dependent on the maternal baseline 25(OH)D status. However, a trend toward the reduction of asthma or recurrent wheezing was observed across the baseline groups in the intervention arm (P = 0.01), with the greatest reduction observed in the most severely vitamin D–deficient women (25(OH)D < 12 ng/mL; adjusted odds ratio [aOR] = 0.48; confidence interval [CI]: 0.17, 1.34). Gestational age at trial enrollment modified supplementation efficacy, showing a greater reduction of offspring asthma or recurrent wheezing with earlier intervention during pregnancy (aOR = 0.85; CI = 0.76, 0.95), particularly in women who were 9–12 wk pregnant (aOR = 0.45; CI = 0.24, 0.82). ConclusionsPregnant women with severe vitamin D deficiency show the greatest 25(OH)D improvement because of supplementation. In these women, a vitamin D dose of 4400 IU might have a preventive role in the development of early life offspring asthma or recurrent wheezing. Gestational age is suggested to modify the efficacy of prenatal vitamin D supplementation, showing the highest beneficial effect if supplementation is started during the first trimester of pregnancy.This study is an ancillary analysis from the VDAART, which is registered in ClinicalTrials.gov as NCT00902621.

138 Preschooler Hemoglobin and Ferritin Concentrations Were Not Affected by Parenting and Multiple Micronutrient Supplementation Interventions in Southwest Guatemala

OBJECTIVES/GOALS: Micronutrient deficiencies contribute to poor health and childhood development outcomes. The objective of this study was to examine the independent and combined effects of responsive parenting and multiple micronutrient supplementation interventions on preschooler hemoglobin and ferritin concentrations in southwestern Guatemala. METHODS/STUDY POPULATION: We enrolled 387 preschoolers (36-52 months) at nutritional risk (height-for-age z-score &lt; -1) (51% male; 17% indigenous ethnicity) in a double blind, 2 x 2, cluster randomized controlled trial. Participants in the parenting intervention received culturally tailored responsive parenting or nutrition education (control) curriculum, delivered over 6 home visits. Participants in the nutrition supplementation group received daily supplementation with a maize-soy product fortified with 21 micronutrients for 6 months or a control product fortified with vitamin B2 only. Linear mixed models were used to estimate changes in hemoglobin and ferritin from baseline (2015) to endline (2017) in a subsample with blood specimens (n = 218). RESULTS/ANTICIPATED RESULTS: At baseline, 14% of preschoolers were iron deficient and 11% were anemic. Preschooler ferritin significantly increased over time in most arms, with the largest increase in the combined responsive parenting + multiple micronutrient supplementation arm (ferritin = 95.6 (95% CI 46.4, 144.74); rates of change did not differ between study arms (p = 0.16). Preschooler hemoglobin did not change over time. Further analysis will examine the moderation of intervention effects by pre-specified child and household factors. DISCUSSION/SIGNIFICANCE: Increases in preschooler ferritin did not differ between intervention and control arms. There was no effect of the intervention on hemoglobin. Future analyses will examine intervention effects on pre-specified subgroups including baseline micronutrient deficiencies.

Abstract P2-06-02: A randomized controlled trial of soy isoflavone intake on mammographic density among Malaysian women

Abstract Introduction: Soy intake is associated with lower breast cancer risk in observational studies of Asian women, but clinical trials of soy isoflavone (ISF) supplements report no effect on biomarkers of breast cancer risk among Caucasian women. To date, there are no such trials among Asian women living in Asia. We conducted a three-armed, randomized controlled trial (RCT) to assess the effects of one-year intervention of soy isoflavone supplements (100mg/day) or soy isoflavones through diet (50mg/day) on mammographic density (MD) change among peri- and postmenopausal Malaysian women. Methodology: Healthy women between 45-65 years old were enrolled between November 2018 and December 2019 at a private tertiary hospital in Malaysia. Women were randomly assigned into the 100mg/day ISF Supplement arm, 50mg/day ISF Diet arm, or Control arm. Dense area was assessed from digital mammograms conducted at enrolment and after 12 months. We compared absolute and relative change in dense area over the study period by study arm using Kruskal Wallis tests. Results: Of the 118 women who received the intervention, 91 women completed the study whilst 27 women (23%) were lost to follow up. After 12 months of intervention, women in the ISF Supplement arm observed a marginally larger decline in dense area (-1.3cm2), compared to women in the ISF Diet arm (-0.5cm2) and Control arm (-0.8cm2), but this difference was not statistically significant (p=0.479). Notably, these effects appear to be stronger and limited to women who enrolled within 5 years of menopause, where up to 6cm2 decline in MD was observed in the ISF Supplement arm, compared to &amp;lt; 1.0cm in the Control arm (p=0.131). Conclusion: This RCT demonstrates a possible causal association between soy ISF intake and lower breast cancer risk among Asian women, specifically around the time of menopause, but these findings will require confirmation in a larger trial. Citation Format: Nadia Rajaram, Beverley Yap, Mikael Eriksson, Shivaani Mariapun, Lee Mei Tan, Hamizah Saat, Evelyn Ho, Nur Aishah Mohd Taib, Geok Lin Khor, Cheng Har Yip, Weang Kee Ho, Per Hall, Soo Hwang Teo. A randomized controlled trial of soy isoflavone intake on mammographic density among Malaysian women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-02.

Effect of 8-week metabolic resistance training and Chlorogenic acid supplement on the expression of UCP1: A randomized clinical trial

Background: Obesity and overweight is one of the major public health challenges all around the world. The aim of this study was to evaluate the simultaneous effect of eight weeks of metabolic resistance training (MRT) and Chlorogenic Acid (CGA) supplementation on weight loss, expression level of UCP1in overweight women. Materials and Methods: The present study was a randomized clinical trial performed in 2022 on a sample of overweight women in Iran. Participants in the study were randomly divided into four groups including combined 8-week course of MRT training and CGA supplementation, 8-week course of MRT, CGA supplement, and the control group. Intervention included three training sessions per week and the duration of each session was 45 minutes. The supplementation arms were also received 400 mg / day CGA extracted from green coffee beans. Expression level of Uncoupling Protein 1 (UCP1) was the main interested outcome that assessed pre and post intervention. Results: In the MRT exercise group, UCP1 expression increased by 4.3 units on average over the 8-week intervention. The highest increase was observed in participants who received both CGA supplement and MRT exercise where UCP1 increased from 22.5 (1.2) to 28.0 (3.5) over the study period (P<0.05). No significant increase was observed in CGA supplementation group. Conclusion: MRT exercises with and without CGA supplementation stimulated expression level of UCP1 mRNA.

The Fish Oil to Reduce Tobacco Use iN Expectant mothers (FORTUNE) feasibility trial

Three small clinical trials have suggested that supplementation with n-3 long-chain polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) found in fish oils may reduce nicotine cravings and at higher doses reduce cigarette consumption. Pregnant women who smoke have fewer pharmacologic options to aid them with smoking cessation. Although n-3 long-chain polyunsaturated fatty acid supplementation has been studied in pregnancy, few studies have evaluated doses of ≥4 g per day, and no previous studies have selectively enrolled pregnant women who smoke. High-dose n-3 long-chain polyunsaturated fatty acids may aid cessation but could be poorly tolerated in pregnant women who smoke because of gastrointestinal side effects. We conducted a feasibility trial to determine the tolerability of high-dose n-3 long-chain polyunsaturated fatty acid supplementation in pregnant women who smoked. We hypothesized that n-3 long-chain polyunsaturated fatty acid doses of 4.2 g a day would be well-tolerated relative to an olive oil placebo. We assessed red blood cell phospholipid membrane concentrations at baseline and end of therapy (4 weeks) and piloted outcomes for a future efficacy trial of n-3 long-chain polyunsaturated fatty acid supplementation for smoking cessation in pregnancy. We recruited 28 pregnant women between the gestational ages of 6 and 36 weeks who reported daily cigarette smoking and were motivated to quit to participate in a double-blind placebo-controlled randomized feasibility trial of 4.2 g per day of n-3 long-chain polyunsaturated fatty acid supplementation. Participants reported cigarettes per day, completed the Fagerström Test for Cigarette Dependence, and provided blood, urine, and exhaled CO samples. We used repeated-measures analysis of variance to pilot analyses of changes in cigarettes per day and Fagerström Test for Cigarette Dependence scores. At baseline, red blood cell membrane eicosapentaenoic acid concentrations were negatively correlated with cigarettes per day (r=-0.44; P=.04). By 4 weeks, circulating n-3 long-chain polyunsaturated fatty acid levels increased by 18% in the n-3 long-chain polyunsaturated fatty acid supplementation arm vs a decrease of 3% in the placebo arm. Occurrence of gastrointestinal side effects such as burping, heartburn, diarrhea, abdominal pain, or nausea did not differ statistically between study arms. At 4 weeks, participants allocated to the n-3 long-chain polyunsaturated fatty acids arm reported a median of 3 cigarettes per day (interquartile range, 1-8) vs 7 cigarettes per day (interquartile range, 1-14) in the placebo arm, which was not statistically significant (P=.99). Participants allocated to the n-3 long-chain polyunsaturated fatty acids arm had a decrease of 1 (interquartile range, 0-1) on the Fagerström Test for Cigarette Dependence score vs 0 (interquartile range, 0-0) for placebo (P=.46). High-dose n-3 long-chain polyunsaturated fatty acids may be tolerated in pregnant women who smoke; however, there was a high level of participant dropout, with more participants allocated to the fish oil arm becoming lost to follow-up. These results will inform the design of a future large-scale randomized controlled trial to test the impact of fish oil supplements on smoking cessation in pregnancy.

A Single Dosage of l-Arginine Oral Supplementation Induced Post-Aerobic Exercise Hypotension in Hypertensive Patients

Lowering of peripheral vascular resistance is one of the primary processes involved in blood pressure decrease. Nitric oxide plays a significant role in this process and the availability of l-arginine is a crucial element in nitric oxide biosynthesis. Oral l-arginine supplementation may therefore be a potentiating element in post-exercise hypotension, mediated by its vasodilator action. Thus, the purpose of this study was to investigate if a single dose of l-arginine oral supplementation might impact the post-aerobic exercise blood pressure responses in treated hypertensive individuals. A double-blind, randomized, placebo-controlled crossover trial was conducted. The sample included male (4) and female (6) subjects [62 ± 10 years]. The participants were randomized to ingest one sachet containing 8 grams of l-arginine or placebo (corn starch) dissolved in water (100 ml). The substances were self-administered 120 min before the experimental or control session. The exercise was conducted on a treadmill and consisted of: a 5 min warm-up (50-65% HRreserve); 40 min of running/walking at 60-70% HRreserve; and a 5 min progressive cooldown. After the exercise sessions, blood pressure was measured every 10 min for 60 min. The l-arginine supplementation arm led to significant post-exercise systolic hypotension (mean post-exercise) in relation to rest period (117 ± 12 vs 125 ± 15 mmHg - p = 0.004 [l-arginine] and 121 ± 11 vs 125 ± 15 - p = 0.341 [placebo]). In addition, a systolic net effect of −6.9 ± 3.6 mmHg [p = 0.046] was identified for the mean post-exercise values. Therefore, this study showed that a single dosage of l-arginine oral supplementation induced post-aerobic exercise hypotension in hypertensive patients.

AHCC® Supplementation to Support Immune Function to Clear Persistent Human Papillomavirus Infections.

ObjectiveTo determine the efficacy, safety, and durability of the use of AHCC supplementation for 6 months to support the host immune system to clear high-risk human papillomavirus (HPV) infections. The AHCC supplement is a proprietary, standardized extract of cultured lentinula edodes mycelia (AHCC®, Amino Up, Ltd., Sapporo, Japan) that has been shown to have unique immune modulatory benefits.Study DesignThis was a randomized, double-blind, placebo-controlled study (CTN: NCT02405533) in 50 women over 30 years of age with confirmed persistent high-risk HPV infections for greater than 2 years. Patients were randomized to placebo once daily for 12 months (N = 25) or AHCC 3-g supplementation by mouth once daily on empty stomach for 6 months followed by 6 months of placebo (N = 25). Every 3 months, patients were evaluated with HPV DNA and HPV RNA testing as well as a blood sample collected to evaluate a panel of immune markers including interferon-alpha, interferon-beta (IFN-β), interferon-gamma (IFN-γ), IgG1, T lymphocytes, and natural killer (NK) cell levels. At the completion of the 12-month study period, patients on the placebo arm were given the option to continue on the study to receive AHCC supplementation unblinded for 6 months with the same follow-up appointments and testing as the intervention arm.ResultsFifty women with high-risk HPV were enrolled, and 41 completed the study. Fourteen (63.6%) of the 22 patients in the AHCC supplementation arm were HPV RNA/HPV DNA negative after 6 months, with 64.3% (9/14) achieving a durable response defined as being HPV RNA/HPV DNA negative 6 months off supplementation. On the placebo arm, two (10.5%) of 19 patients were HPV negative at 12 months. In the twelve placebo arm patients who elected to continue on the unblinded study, 50% (n = 6) were HPV RNA/HPV DNA negative after 6 months of AHCC supplementation. At the time of completion of the study, there were a total of 34 patients (22 blinded and 12 unblinded) who had received AHCC supplementation with an overall response rate of 58.8% that cleared HPV persistent infections. At the time of enrollment, the mean IFN-β level was 60.5 ± 37.6 pg/ml in women with confirmed persistent HPV infections. Suppression of IFN-β to less than 20 pg/ml correlated with an increase in T lymphocytes and IFN-γ and durable clearance of HPV infections in women who received AHCC supplementation.ConclusionResults from this phase II study demonstrated that AHCC 3 g once daily was effective to support the host immune system to eliminate persistent HPV infections and was well tolerated with no significant adverse side effects reported. The duration of AHCC supplementation required beyond the first negative result needs more evaluation to optimize success for durable outcomes. The suppression of the IFN-β level to less than 20 pg/ml correlated with clearance of HPV infections and merits further evaluation as a clinical tool for monitoring patients with HPV infections.Clinical Trial Registrationclinicaltrials.gov/ct2/, identifier NCT02405533

510 Independent and Combined Effectiveness of Multiple Micronutrient Supplementation and Responsive Caregiving Interventions to Support Early Child Development in Southwest Guatemala

OBJECTIVES/GOALS: The objective of this study is to examine the independent and combined effectiveness of a multiple micronutrient supplementation and responsive caregiving intervention on early child development in southwestern Guatemala. METHODS/STUDY POPULATION: We conducted a double blind, 2 x 2, cluster randomized controlled trial combining micronutrient supplementation and responsive caregiving treatments. We enrolled 309 infants (6-18 months) and 387 preschoolers (36-52 months) at nutritional risk (height-for-age z-score &lt; -1) (51% male; 17% indigenous ethnicity; 76% of caregivers completed ≤ primary school). The supplementation arm received a maize-soy product fortified with 21 micronutrients for 6 months; the control was fortified with B2. The responsive caregiving intervention was adapted from the UNICEF Care for Child Development program and delivered over 6 home visits. We examined changes in early child development from baseline (2015) to endline (2017) using the Bayley Scales of Infant and Toddler Development III and Bracken Scales of School Readiness. RESULTS/ANTICIPATED RESULTS: Among infants, age standardized Bayley cognitive development scores declined over time in each treatment arm. Infant Bayley motor development scores significantly increased in the combined multiple micronutrient supplementation + responsive caregiving arm (â^† = 3.67 [95% CI: 0.17, 7.17], p = 0.04). Among preschoolers, school readiness decreased over time in each treatment arm. The rates of change in infant development and preschooler school readiness did not differ between treatment arms. Further analysis will explore effect modification of the intervention by pre-specified child and household factors. DISCUSSION/SIGNIFICANCE: Combined multiple micronutrient supplementation and responsive caregiving supported motor development while cognitive and school readiness were not impacted by the intervention. These findings will inform the effectiveness and beneficiaries of multisectoral interventions to promote early child development in adverse environments.

Comparison of Infant Bone Mineral Content and Density After Infant Daily Oral Vit D 400 IU Supplementation Versus Nursing Mother Oral 6,400 IU Supplementation: A Randomized Controlled Lactation Study.

Background: Vitamin D (vitD) plays a major role in maintenance of bone mineral homeostasis. It is unknown if bone mineral content (BMC) and bone mineral density (BMD) differ between infants who receive direct vitD supplementation and those who receive vitD indirectly via their mother's breast milk, while she received a high dose of vitD. It is hypothesized that there would be no differences in BMC or BMD by treatment group. Design/Methods: Randomized, double-blind trial to compare BMD and BMC of infants who received direct vitD (400 IU vitD3/day) in addition to their mother receiving standard dosage (400 IU vitD3/day) versus infants whose mothers were their only source of vitD and were given high-dose supplementation (6,400 IU vitD3/day). Participants were exclusively breastfeeding mothers and their infant consuming only human milk. Infant BMC and BMD were measured by dual-energy X-ray absorptiometry (DXA) scans of the infant's total body using Hologic Discovery A Densitometer and analyzed using Hologic Infant software at 1, 4, and 7 months of age. Results: Infant BMC and BMD did not differ significantly at 1, 4, or 7 months of age between direct and indirect supplementation arms. The mean difference in BMC from 1 to 7 months was 1.624 and 1.464 g for the 400 and 6,400 IU groups, respectively, (p = 0.5); the mean difference in BMD over this same period was 0.042 and 0.032 g/cm2 for the 400 and 6,400 IU groups, respectively (p = 0.2). Although some differences among races were observed, this did not reflect changes in bone growth between the treatment arms. Conclusion: High-dose vitD supplementation of mothers during lactation provided an efficacious alternative to direct supplementation of infants, as evidenced by noninferior infant BMD and BMC. Clinical Trial Registration number: NCT00412074.

Prevention of leg cramps by using compression stockings or magnesium supplements in the 50\u201384 age group: study protocol for a randomised controlled trial

BackgroundLeg cramps are painful sensations of tightening in the muscles of the legs that commonly appear during the night and are often associated with secondary insomnia. They are common especially in older age. There is no evidence that any method of prevention of nocturnal leg cramps is both safe and effective. There are no previous trials concerning cramp prevention by using compression stockings. The objective of this study is to assess in a prospective randomised controlled trial whether leg cramps can be prevented by the daily use of knee-length compression stockings or magnesium supplements.MethodsThe study will be set in Finland, and 50–84-year-old volunteers will be recruited through Google Ads, the Finnish health library website and Finnish primary health care centres. The participants must have a minimum of two episodes of leg cramps per week for the past 4 weeks to be included in the study. The participants (n = 225) will be allocated to three equal groups: the compression stocking arm, the magnesium supplement arm and the placebo arm. The participants will go through 4 weeks of follow-up without intervention and then another 4 weeks of follow-up with the assigned intervention. The material for the study will be collected through electronic questionnaires.DiscussionThis protocol describes a study that compares compression stockings, magnesium supplements and placebo for the prevention of leg cramps. The results of this study can significantly improve knowledge on the methods of preventing leg cramps.Trial registrationClinicalTrials.gov NCT04694417. Registered on Jan 4, 2021.

Improved first trimester maternal iodine status with preconception supplementation: The Women First Trial.

Maternal iodine (I) status is critical in embryonic and foetal development. We examined the effect of preconception iodine supplementation on maternal iodine status and on birth outcomes. Non‐pregnant women in Guatemala, India and Pakistan (n ~ 100 per arm per site) were randomized ≥ 3 months prior to conception to one of three intervention arms: a multimicronutrient‐fortified lipid‐based nutrient supplement containing 250‐μg I per day started immediately after randomization (Arm 1), the same supplement started at ~12 weeks gestation (Arm 2) and no intervention supplement (Arm 3). Urinary I (μg/L) to creatinine (mg/dl) ratios (I/Cr) were determined at 12 weeks for Arm 1 versus Arm 2 (before supplement started) and 34 weeks for all arms. Generalized linear models were used to assess the relationship of I/Cr with arm and with newborn anthropometry. At 12 weeks gestation, adjusted mean I/Cr (μg/g) for all sites combined was significantly higher for Arm 1 versus Arm 2: (203 [95% CI: 189, 217] vs. 163 [95% CI: 152, 175], p < 0.0001). Overall adjusted prevalence of I/Cr < 150 μg/g was also lower in Arm 1 versus Arm 2: 32% (95% CI: 26%, 38%) versus 43% (95% CI: 37%, 49%) (p = 0.0052). At 34 weeks, adjusted mean I/Cr for Arm 1 (235, 95% CI: 220, 252) and Arm 2 (254, 95% CI: 238, 272) did not differ significantly but were significantly higher than Arm 3 (200, 95% CI: 184, 218) (p < 0.0001). Nominally significant positive associations were observed between I/Cr at 12 weeks and birth length and head circumference z‐scores (p = 0.028 and p = 0.005, respectively). These findings support the importance of first trimester iodine status and suggest need for preconception supplementation beyond salt iodization alone.

Vitamin C supplementation improves blood pressure and oxidative stress after acute exercise in patients with poorly controlled type 2 diabetes mellitus: A randomized, placebo-controlled, cross-over study.

This study aimed to assess the effect of Vitamin C on blood pressure (BP), and subsequently on oxidative stress and nitric oxide (NO) release, following the low-intensity exercise in the patients. This study included 24 patients with type 2 diabetes mellitus (T2D) (age, 53 ± 7 years; hemoglobin A1c, 10.1% ± 0.9%) randomized into two 6-week daily arms based on the consumption of either placebo or 1000 mg Vitamin C. The crossover trial occurred after a 6-week washout. Before and after both supplementation arms, all patients performed cycling exercise at 33% of peak oxygen consumption for 20 min. BP was measured before, immediately, and 60 min after the exercise. Blood samples were drawn immediately before and after the exercise to determine plasma ascorbate, malondialdehyde (MDA), F2-isoprostanes (F2-IsoPs), and NO concentrations. Data showed significant lower BP in the Vitamin C arm when compared with the placebo arm (systolic BP [SBP] P < 0.001 at every time point, diastolic BP [DBP] P < 0.001 except at immediately after exercise, P < 0.05). Plasma ascorbate concentration (P < 0.05 at every time point) and plasma NO (at resting P < 0.001, immediately after exercise P < 0.05) were significantly increased in the Vitamin C arm than in the placebo arm. Plasma MDA (P < 0.05 at every time point) and F2-IsoPs (P < 0.05 at every time point) concentrations were significantly lower in the Vitamin C arm than in the placebo arm. In addition, data showed significantly lower SBP (P < 0.001 at every time point), DBP (P < 0.001 except at immediately after exercise P < 0.05), plasma MDA (P < 0.001 at every time point), and F2-IsoPs (P < 0.05 at every time point) at post-supplementation than at pre-supplementation. Besides, there were significantly higher plasma ascorbate (P < 0.05 at every time point) and NO (at rest P < 0.01, immediately after exercise P < 0.05) concentrations at post-supplementation than at pre-supplementation. This is in contrast to the placebo treatment arm which demonstrated no statistical difference in all outcomes throughout the experiment. This study suggests that 6-week Vitamin C supplementation decreased preexercise and postexercise BPs, possibly due to improved oxidative stress and NO release. However, exercise had no effect on any outcome measures.

Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation

BackgroundEicosapentaenoic acid (EPA) supplementation is an effective treatment option in major depressive disorder (MDD) associated with chronic low-grade inflammation. EPA is the precursor of specialized pro-resolving lipid mediators (SPMs) termed resolvins (Rv), that serve important roles in the resolution of inflammation. The objective of this study was to assess the effects of different doses of EPA on plasma concentrations of EPA metabolites and SPMs in MDD patients. MethodsIn a 2-site study, 61 MDD patients with body mass index >25 kg/m2 and serum high-sensitivity C-reactive protein ≥3 μg/mL were enrolled in a 12-week randomized trial comparing EPA 1, 2, and 4 g/d to placebo. Plasma EPA (mol%) and SPMs (pg/mL) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. ResultsPlasma EPA and SPM concentrations did not change in the placebo group during 12 weeks of treatment. Plasma EPA and EPA-derived metabolites increased significantly and dose-dependently in all EPA supplementation arms. The increase in 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor of RvE1–3, was significantly greater with the 4 g/d EPA dose than the other doses from week 4 to 12. RvE1 was undetected in all treatment groups, while RvE2 was detected in half of the subjects both at baseline and after treatment, with dose-dependent increases. RvE3 was detected only after supplementation, dose-dependently. A significant reduction in plasma arachidonic acid (AA), relative to baseline, was observed in all EPA arms. This was in contrast with an increase in AA-derived SPM lipoxin B4 (LXB4) in the 4 g/d arm. ConclusionsOur results show a robust effect of EPA 4 g/d supplementation in increasing plasma EPA and 18-HEPE levels, associated with improved conversion to RvE2–3, and LXB4 levels.

Growth from Birth Through Six Months for Infants of Mothers in the “Women First” Preconception Maternal Nutrition Trial

To evaluate whether the fetal linear growth effects of maternal nutrition supplementation would be maintained through 6months postnatal age. The Women First trial was a multicountry, individually randomized clinical trial that compared the impact of maternal nutrition supplementation initiated preconception (Arm 1) vs at ∼11weeks of gestation (Arm 2), vs no supplement (Arm 3); the intervention was discontinued at delivery. Trial sites were in Democratic Republic of Congo, Guatemala, India, and Pakistan. Analysis includes 2421 infants born to 2408 randomized women. Primary outcome was the trajectory of length-for-age z scores (LAZ) by arm, based on assessments at birth and 1, 3, and 6months. We fitted longitudinal models on growth from birth to 6months using generalized estimating equations; maternal intervention effects were evaluated, adjusting for site and baseline maternal covariates. Linear growth for Arms 1 and 2 was statistically greater than for Arm 3 in 3 of the 4 countries, with average pairwise mean differences in LAZ of 0.25 (95% CI 0.15-0.35; P<.001) and 0.19 (95% CI 0.09-0.28; P<.001), respectively. Compared with Arm 3, average overall adjusted relative risks (95% CI) for stunting (LAZ <-2) were lower for Arms 1 and 2: 0.76 (0.66-0.87; P<.001) and 0.77 (0.67-0.88; P<.001), respectively. Improved linear growth in early infancy observed for the 2 intervention arms supports the critical importance of maternal nutrition before conception and in the early phase of gestation. ClinicalTrials.gov: NCT01883193.

Vitamin D supplementation in obese Sri Lankan children: a randomized controlled trial

BackgroundMicronutrient deficiencies are identified among obese individuals. Vitamin D deficiency (VDD) is prevalent in obese children, and is hypothesized to cause insulin resistance and metabolic abnormalities. This study aimed to determine the effect of vitamin D supplementation on obesity and related metabolic abnormalities among obese Sri Lankan children with VDD.MethodsA triple-blind randomized controlled trial was conducted among vitamin D deficient (< 20 ng/ml), obese children (n = 96), randomly allocated to three intervention arms - treatment arm receiving weekly vitamin D2 50,000 IU; supplementation arm receiving 2500 IU weekly and control arm, receiving placebo. Anthropometry, percentage fat mass (%FM) and blood pressure were assessed and fasting blood glucose, fasting insulin, lipid profile, aspartate transaminase (ALT), alanine transaminase (AST), vitamin D, parathyroid hormone (PTH) and hs-CRP and OGTT with 2-h random blood glucose and insulin was performed at baseline and after 24 weeks of treatment. Ethics Review Committee of Faculty of Medicine, University of Colombo approved the protocol.ResultsWaist circumference Z-score, %FM and serum calcium significantly improved across all three arms, ALT significantly improved in treatment and supplementation arms while, BMI Z-score, PTH and vitamin D significantly improved in the treatment arm. Biceps (p = 0.035) and subscapular (0.048) skin fold thickness, vitamin D (p = 0.004) and ALT (p = 0.012) significantly improved in the treatment arm.ConclusionsA strict dietary and physical activity regimen could improve some of the anthropometric, body composition and metabolic profiles, but high dose vitamin D, enhances those improvements. Therefore high dose vitamin D seems to potentiate management outcomes of obese children with vitamin D deficiency.Trial registrationThe study was registered at the Sri Lanka Clinical Trials Registry (SLCTR/2015/017) on 12th September 2015 at https://slctr.lk/trials/slctr-2015-017.

Analysis of Interest Deduction Rules Under Ethiopian Corporate Tax System

The use of third party and related party interest is one of the profit-shifting techniques available in international tax planning. The fluidity and fungibility of money make it a relatively simple exercise to adjust the mix of debt and equity in a controlled company. When the level of debt capital is much greater than the equity capital of the company thin capitalization occurs. Nowadays, thin capitalization is one of the major challenges to the corporate tax system of Ethiopia. Thin capitalization reduces government income from tax by increasing deductible interest paid or payable on the debt. To address this problem, Ethiopia has implemented tax rules restricting the deductibility of interest payments. This article aims to qualitatively examine the interest deduction rules under the Ethiopian income tax regimes through a qualitative analysis of existing literatures and laws. To this end, the analysis start unfolding the conceptual framework of interest deduction and its rules followed by an examination of interest deduction rules of Ethiopia. As the finding has revealed, the newly enacted federal income law has taken a big step in tightening the interest deduction rules through the adoption of debt-to-equity ratio and arm’s length approach to determine the maximum debt on which interest deductible. In doing so, the income tax rules of Ethiopia incorporated the indirect interest deduction rule which indirectly limits the amount interest on which is deduction is allowable. In addition to this, the withholding tax imposed on interest paid to non-resident and limit on maximum deductible interest rates are adopted as an interest deduction approach to supplement arm’s length and debt-to-equity ratio to protect tax base erosion. Despite these positive developments, the Ethiopian tax law has failed to recognize direct interest deduction rules which directly limit the maximum interest on which deduction is allowed. Nowadays, interest stripping rule is widely appreciated as the modern and most effective approach that directly restricts interest deduction. So, the failure to introduce a direct interest deduction rule is one of the major defect interest deduction rules in Ethiopia. Besides, the income tax law has failed to limit the special debt-equity ratio that applies to financial institutions. Furthermore, the tax law has failed to set a maximum deductible rate that applies to financial institutions licensed to lend in Ethiopia. To fill these gaps and ensure efficient protection of the tax base against erosion by deduction of interest payment, the researcher called for a direct interest deduction rule. Besides, the researcher called for the introduction of the debt-equity ratio that applies to a financial institution and the maximum deductible interest rate concerning the interest payment to legitimate financial institutions.