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Safety and efficacy of a probiotic-containing infant formula supplemented with 2'-fucosyllactose: a double-blind randomized controlled trial.
Alliet, P, Vandenplas, Y, Roggero, P, Jespers, SNJ, Peeters, S, Stalens, JP, Kortman, GAM, Amico, M, Berger, B, Sprenger, N, et al
Nutrition journal. 2022;(1):11
Abstract
BACKGROUND Human milk oligosaccharides (HMOs) have important and diverse biological functions in early life. This study tested the safety and efficacy of a starter infant formula containing Limosilactobacillus (L.) reuteri DSM 17938 and supplemented with 2'-fucosyllactose (2'FL). METHODS Healthy infants < 14 days old (n = 289) were randomly assigned to a bovine milk-based formula containing L. reuteri DSM 17938 at 1 × 107 CFU/g (control group; CG) or the same formula with added 1.0 g/L 2'FL (experimental group; EG) until 6 months of age. A non-randomized breastfed group served as reference (BF; n = 60). The primary endpoint was weight gain through 4 months of age in the formula-fed infants. Secondary endpoints included additional anthropometric measures, gastrointestinal tolerance, stooling characteristics, adverse events (AEs), fecal microbiota and metabolism, and gut immunity and health biomarkers in all feeding groups. RESULTS Weight gain in EG was non-inferior to CG as shown by a mean difference [95% CI] of 0.26 [-1.26, 1.79] g/day with the lower bound of the 95% CI above the non-inferiority margin (-3 g/day). Anthropometric Z-scores, parent-reported stooling characteristics, gastrointestinal symptoms and associated behaviors, and AEs were comparable between formula groups. Redundancy analysis indicated that the microbiota composition in EG was different from CG at age 2 (p = 0.050) and 3 months (p = 0.052), approaching BF. Similarly, between sample phylogenetic distance (weighted UniFrac) for BF vs EG was smaller than for BF vs CG at 3-month age (p = 0.045). At age 1 month, Clostridioides difficile counts were significantly lower in EG than CG. Bifidobacterium relative abundance in EG tracked towards that in BF. Fecal biomarkers and metabolic profile were comparable between CG and EG. CONCLUSION L. reuteri-containing infant formula with 2'FL supports age-appropriate growth, is well-tolerated and may play a role in shifting the gut microbial pattern towards that of breastfed infants. TRIAL REGISTRATION The trial was registered on ClinicalTrials.gov ( NCT03090360 ) on 24/03/2017.
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A randomized, controlled, blinded, parallel group, clinical trial to study the role of Ayurcov (AyurCoro3), one day regimen as an adjuvant therapy for COVID-19 disease management, at dedicated Covid Hospital (DCH) in India.
Sankhe, AP, Memane, NS, Gawali, VP, Memane, SN, Ramakrishnan, G, Kundu, T, Bagul, MN, Kumar, A, Bansal, V, Tiwari, R
Complementary therapies in medicine. 2022;:102824
Abstract
INTRODUCTION Limited treatment options exist for COVID-19 infections; thus, attempts from complementary and alternative systems (CAM) of medicine are being explored as possible therapeutic options. Ayurcov is a formulation made of ingredients mentioned in Ayurveda. These constituents have proven antiviral, detoxifying, immune-modulating, and bio-enhancing properties. The present study was carried out to evaluate the therapeutic effect and safety of Ayurcov in patients with various severity states of COVID-19 infections. METHODS A randomized, single blinded, controlled trial was carried out in adults diagnosed with mild-to-moderate, and severe COVID-19 infections confirmed by real time reverse transcriptase polymerase chain reaction (rRTPCR) test. The interventional group received three doses of 'Ayurcov'. It is constituted of Haridra Churna (Curcuma longa), Go ark (Bos Indicus Distilled Urine), Sphatika (Alum), Sita (Rock Candy), Godugdham (Bos Indicus Milk) milk, Goghritam (Bos Indicus ghee) on Day 1, as an adjuvant to the standard of care, and the control group received only the standard of care. Key outcomes included: proportion of patients and time taken for symptom resolution, reduction in the rRT-PCR Ct values, safety, and functional status until 42 days after discharge. RESULTS Ninety patients with mild-to-moderate and 30 patients with severe COVID-19 disease were recruited. It was observed that significantly more proportions of patients receiving Ayurcov had symptom relief much earlier than control group. Additionally, the interventional group showed significantly lower rRT-PCR Ct values. However, a shorter time of resolution of symptoms was observed with the interventional group in the mild to moderate category but not with those having severe symptoms. Similarly, a significantly better functional status was observed with interventional group on days 7 and 28 after discharge. Ayurcov was not observed with higher risks of any adverse/serious adverse events. CONCLUSIONS Ayurcov as adjuvant with standard of care was associated with significantly earlier resolution of COVID-19 related symptoms than standard of care alone.
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Omega-3 fatty acids and blood-based biomarkers in Alzheimer's disease and mild cognitive impairment: A randomized placebo-controlled trial.
Lin, PY, Cheng, C, Satyanarayanan, SK, Chiu, LT, Chien, YC, Chuu, CP, Lan, TH, Su, KP
Brain, behavior, and immunity. 2022;:289-298
Abstract
BACKGROUND Increased serum levels of pro-inflammatory biomarkers are consistently associated with cognitive decline. The omega-3 unsaturated fatty acids (n-3 PUFAs) had been linked to slowing cognitive decline due to their potential anti-inflammatory effects. To our knowledge, the different regiments of pure DHA, pure EPA, and their combination on various associated symptoms of dementia, including a mild form of cognitive impairment (MCI) and Alzheimer's disease (AD), have never been studied. METHODS This multisite, randomized, double-blind, placebo-controlled trial was conducted at two veteran's retirement centers and one medical center in central Taiwan between 2013 and 2015. 163 MCI or AD patients were randomly assigned to placebo (n = 40), docosahexaenoic acid (DHA, 0.7 g/day, n = 41), eicosapentaenoic acid (EPA, 1.6 g/day, n = 40), or EPA (0.8 g/day) + DHA (0.35 g/day) (n = 42) group for 24 months. The results were measured as the cognitive and functional abilities, biochemical, and inflammatory cytokines profiles. Chi-square tests, two-sample t-test, ANOVA, and linear mixedeffects models were conducted with p < 0.05. RESULTS 131 (80%) participants had completed the trial with all cognitive, functional, and mood status assessments. The statistically significant difference between the placebo and treatment groups was not determined, concerning the changes in cognitive, functional, and mood status scores, the biochemical profiles, and inflammatory cytokines levels. However, EPA was found to reduce the C-C motif ligands 4 (CCL4) level (p < 0.001). Additionally, EPA could reduce the constructional praxis (p < 0.05) and spoken language ability scores (p < 0.01), and DHA also reduced the spoken language ability score (p < 0.05). CONCLUSION Overall, n-3 PUFAs supplements did not reduce cognitive, functional, and depressive symptom outcomes, but spoken language ability and constructional praxis subitems of ADAS-cog. These findings show that attention to clinical heterogeneity in dementia is crucial when studying nutrients interventions, such as n-3 PUFAs. In addition, with small effect size CCL4 is a better indicator than other inflammatory cytokines for EPA treatment response.
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Long-term follow-up of patients treated with caplacizumab and safety and efficacy of repeat caplacizumab use: Post-HERCULES study.
Scully, M, de la Rubia, J, Pavenski, K, Metjian, A, Knöbl, P, Peyvandi, F, Cataland, S, Coppo, P, Kremer Hovinga, JA, Minkue Mi Edou, J, et al
Journal of thrombosis and haemostasis : JTH. 2022;(12):2810-2822
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Abstract
INTRODUCTION Caplacizumab demonstrated efficacy and safety in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in the phase 3 HERCULES trial. However, data on long-term outcomes following caplacizumab treatment are limited. OBJECTIVES The post-HERCULES trial (NCT02878603) evaluated long-term outcomes of patients with iTTP treated with caplacizumab in HERCULES and safety and efficacy of repeated caplacizumab use. PATIENTS/METHODS Over 3 years of follow-up, patients could receive open-label caplacizumab with therapeutic plasma exchange (TPE) and immunosuppressive therapy (IST) in case of recurrence. Adverse events (AEs) were assessed during the overall study period (intention-to-observe [ITO] population) and during recurrences (recurrence population). TTP-related events (TTP-related death, recurrence, major thromboembolic events) were assessed in the efficacy ITO population (patients without recurrence during HERCULES or before post-HERCULES). RESULTS Among 104 enrolled patients, incidences of AEs and serious AEs were similar between patients who had received caplacizumab + TPE + IST during HERCULES (n = 75) and those treated with placebo + TPE + IST (placebo; n = 29). TTP-related events occurred in 8% of patients (4/49) randomized to caplacizumab during HERCULES versus 38% (11/29) randomized to placebo. Nineteen patients had ≥1 recurrence; 13 of these were treated with caplacizumab. The first recurrence episode was resolved or resolving for all patients treated with caplacizumab, including nine patients with repeat caplacizumab use. All second recurrences (6/6) were resolved. Safety profile of caplacizumab for treatment of recurrence was consistent with HERCULES; most bleeding events were nonserious. No major cases of organ dysfunction were observed. CONCLUSIONS Long-term follow-up supports the safety and efficacy of caplacizumab for iTTP and its repeated use for recurrences.
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Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age.
Creech, CB, Anderson, E, Berthaud, V, Yildirim, I, Atz, AM, Melendez Baez, I, Finkelstein, D, Pickrell, P, Kirstein, J, Yut, C, et al
The New England journal of medicine. 2022;(21):2011-2023
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BACKGROUND Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown. METHODS Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 μg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. RESULTS In part 1 of the trial, 751 children received 50-μg or 100-μg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-μg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 μg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-μg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-μg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. CONCLUSIONS Two 50-μg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).
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Effects of Dietary Supplementation with Carrot-Derived Rhamnogalacturonan-I (cRG-I) on Accelerated Protective Immune Responses and Quality of Life in Healthy Volunteers Challenged with Rhinovirus in a Randomized Trial.
McKay, S, Teitsma-Jansen, A, Floris, E, Dekker, T, Smids, B, Khurshid, R, Calame, W, Kardinaal, A, Lutter, R, Albers, R
Nutrients. 2022;(20)
Abstract
An adequate and balanced supply of nutrients is essential for maintaining health, and an optimal immune response is fast, contained and properly controlled, curbing infections quickly while minimizing damage. Several micronutrients contribute to normal immune function and certain dietary fibers, for example pectic polysaccharides, can play an important role in educating and regulating immune cell responses. The aim of this paper is to elaborate on our initial findings that dietary supplementation with carrot-derived rhamnogalacturonan-I (cRG-I) accelerates and augments local innate immune and anti-viral interferon response to a rhinovirus-16 (RV16) infection and reduces the severity and duration of symptoms in humans. Dietary intake of cRG-I also enhanced immune responses to this respiratory viral infection as measured by ex vivo stimulation of whole blood with the Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid and NK cell function. Consumption of cRG-I also reduced the negative effects of this common cold infection on quality of life as assessed by individual symptom scores. RG-I from carrot is a safe, sustainable, and economically viable solution that could easily be integrated into food products and dietary supplements aiming to support immune fitness and wellbeing.
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Probiotic effects on immunity and microbiome in HIV-1 discordant patients.
Blázquez-Bondia, C, Parera, M, Català-Moll, F, Casadellà, M, Elizalde-Torrent, A, Aguiló, M, Espadaler-Mazo, J, Santos, JR, Paredes, R, Noguera-Julian, M
Frontiers in immunology. 2022;:1066036
Abstract
BACKGROUND Some HIV-1 infected patients are unable to completely recover normal CD4+ T-cell (CD4+) counts after achieving HIV-1 suppression with combined Antiretroviral Therapy (cART), hence being classified as immuno-discordant. The human microbiome plays a crucial role in maintaining immune homeostasis and is a potential target towards immune reconstitution. SETTING RECOVER (NCT03542786) was a double-blind placebo-controlled clinical trial designed to evaluate if the novel probiotic i3.1 (AB-Biotics, Sant Cugat del Vallès, Spain) was able to improve immune reconstitution in HIV-1 infected immuno-discordant patients with stable cART and CD4+ counts <500 cells/mm3. The mixture consisted of two strains of L. plantarum and one of P. acidilactici, given with or without a fiber-based prebiotic. METHODS 71 patients were randomized 1:2:2 to Placebo, Probiotic or probiotic + prebiotic (Synbiotic), and were followed over 6 months + 3-month washout period, in which changes on systemic immune status and gut microbiome were evaluated. Primary endpoints were safety and tolerability of the investigational product. Secondary endpoints were changes on CD4+ and CD8+ T-cell (CD8+) counts, inflammation markers and faecal microbiome structure, defined by alpha diversity (Gene Richness), beta diversity (Bray-Curtis) and functional profile. Comparisons across/within groups were performed using standard/paired Wilcoxon test, respectively. RESULTS Adverse event (AE) incidence was similar among groups (53%, 33%, and 55% in the Placebo, Probiotic and Synbiotic groups, respectively, the most common being grade 1 digestive AEs: flatulence, bloating and diarrhoea. Two grade 3 AEs were reported, all in the Synbiotic group: abdominal distension (possibly related) and malignant lung neoplasm (unrelated), and 1 grade 4 AE in the Placebo: hepatocarcinoma (unrelated). Synbiotic exposure was associated with a higher increase in CD4+/CD8+ T-cell (CD4/CD8) ratio at 6 months vs baseline (median=0.76(IQR=0.51) vs 0.72(0. 45), median change= 0.04(IQR=0.19), p = 0.03). At month 9, the Synbiotic group had a significant increase in CD4/CD8 ratio (0.827(0.55) vs 0.825(0.53), median change = 0.04(IQR=0.15), p= 0.02) relative to baseline, and higher CD4+ counts (447 (157) vs. 342(73) counts/ml, p = 0.03), and lower sCD14 values (2.16(0.67) vs 3.18(0.8), p = 0.008) than Placebo. No effect in immune parameters was observed in the Probiotic arm. None of the two interventions modified microbial gene richness (alpha diversity). However, intervention as categorical variable was associated with slight but significant effect on Bray-Curtis distance variance (Adonis R2 = 0.02, p = 0.005). Additionally, at month 6, Synbiotic intervention was associated with lower pathway abundances vs Placebo of Assimilatory Sulphate Reduction (8.79·10-6 (1.25·10-5) vs. 1.61·10-5 (2.77·10-5), p = 0.03) and biosynthesis of methionine (2.3·10-5 (3.17·10-5) vs. 4·10-5 (5.66·10-5), p = 0.03) and cysteine (1.83·10-5 (2.56·10-5) vs. 3.3·10-5 (4.62·10-5), p = 0.03). At month 6, probiotic detection in faeces was associated with significant decreases in C Reactive Protein (CRP) vs baseline (11.1(22) vs. 19.2(66), median change= -2.7 (13.2) ug/ml, p = 0.04) and lower IL-6 values (0.58(1.13) vs. 1.17(1.59) ug/ml, p = 0.02) when compared with samples with no detectable probiotic. No detection of the probiotic was associated with higher CD4/CD8 ratio at month 6 vs baseline (0.718(0.57) vs. 0.58(0.4), median change = 0.4(0.2), p = 0.02). After washout, probiotic non-detection was also associated with a significant increase in CD4+ counts (457(153) vs. 416(142), median change = 45(75), counts/ml, p = 0.005) and CD4/CD8 ratio (0.67(0.5) vs 0.59(0.49), median change = 0.04 (0.18), p = 0.02). CONCLUSION A synbiotic intervention with L. plantarum and P. acidilactici was safe and led to small increases in CD4/CD8 ratio and minor reductions in sCD14 of uncertain clinical significance. A probiotic with the same composition was also safe but did not achieve any impact on immune parameters or faecal microbiome composition.
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Primary care experience on Stimunex® gocce in children with recurrent respiratory infections: a real-world study during the COVID-19 pandemic era.
Giannattasio, A, Poggi, E, Trapani, G, Muia, C, Zanino, L, Landi, M, Ciprandi, G
Allergologia et immunopathologia. 2022;(3):8-14
Abstract
BACKGROUND Respiratory infections (RI) significantly burden society, mainly when there are recurrent respiratory infections (RRI). Thus, there is a need to prevent RI in clinical practice. In this regard, the modulation of the immune system and resolution of the inflammatory cascade could represent an ideal way to prevent RI. Stimunex® gocce, a multicomponent food supplement, contains Sambucus nigra extract, β-glucan, Zinc, and Vitamin D3. This study investigated its ability to prevent RRI in children using a real-world setting: the pediatric primary care. MATERIALS AND METHODS Two hundred and ninety-eight children with RRI were enrolled in the current study. The food supplement was randomly prescribed to 160 children with RRI daily for 4 months (Active group); the remaining 138 children with RRI were treated only with standard therapy for RI (Control group). The number and duration of RI, parental perception of symptom severity and treatment efficacy, use of medications, and school and working absence were evaluated. RESULTS Children treated with Stimunex® gocce had significantly less RI than the Control group, both concerning upper and lower RI (p˂0.001 and 0.003, respectively) during the follow-up period. Moreover, children in the Active group experienced shorter RI duration during the treatment and follow-up phases (p˂0.001 for both). In addition, parents of treated children perceived less severe symptoms and better treatment efficacy during the first and follow-up phases (p˂0.001 for all). The food supplement was well tolerated and there was no adverse event. CONCLUSIONS The current real-world study demonstrated that Stimunex® gocce supplementation in children with RRI might safely prevent RI episodes and reduce RI duration. These outcomes should be highlighted as obtained during the COVID-19 pandemic era, characterized by a dramatic reduction of RI.
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Changes in Non-Deamidated versus Deamidated Epitope Targeting and Disease Prediction during the Antibody Response to Gliadin and Transglutaminase of Infants at Risk for Celiac Disease.
Diós, Á, Srinivasan, B, Gyimesi, J, Werkstetter, K, Valenta, R, Koletzko, S, Korponay-Szabó, IR
International journal of molecular sciences. 2022;(5)
Abstract
Celiac disease (CeD) is a conditional autoimmune disorder with T cell-mediated immune response to gluten coupled with antibody production to gliadin and the self-protein tissue transglutaminase (TG2). TG2 contributes to the CeD pathomechanism by deamidating gliadin, thereby generating more immunogenic peptides. Anti-gliadin antibodies may appear before the autoantibody production. The scope of this study was to dissect these early antibody responses by investigating serum samples collected during the PreventCD prospective double-blind study, where infants with high CeD risk were randomized to 200 mg daily gluten intake or placebo from 4 to 6 months of age, followed by frequent blood testing on regular gluten consumption in both groups. After primary gluten intake, children with or without later CeD produced IgA and IgG antibodies which preferentially recognized non-deamidated gliadin peptides. At CeD development with anti-TG2 seroconversion, there was a significant increase in the antibody reaction toward deamidated gliadin peptides (DGP), with maturation in the binding strength for the PEQPFP gamma-gliadin core peptide. The earliest produced autoantibodies targeted TG2's celiac epitope 2. Our results reveal a qualitative change in the gliadin-directed humoral immune response at the time when anti-TG2 antibodies appear, but anti-DGP antibodies in the absence of anti-TG2 antibodies are not disease-predictive.
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Significant decrease in plasmad-dimer levels and mean platelet volume after a 3-month treatment with rosuvastatin in patients with venous thromboembolism.
Alirezaei, T, Sattari, H, Irilouzadian, R
Clinical cardiology. 2022;(7):717-722
Abstract
BACKGROUND Inflammation has been considered as a possible mechanism for the initiation and recurrence of venous thromboembolism (VTE). Statins have anti-inflammatory and potential immune-modulatory effects, but their effect on plasmad-dimer levels is controversial. HYPOTHESIS In this study, we aimed to evaluate the impact of rosuvastatin on D-dimer and other inflammatory serum markers in VTE patients. METHODS We conducted a prospective, randomized study on 228 patients with VTE. Control group received conventional treatment (warfarin or rivaroxaban), whereas rosuvastatin-intervention group received rosuvastatin 10 mg daily, in addition to their conventional treatment for 3 months. Serum markers were extracted from both groups at the baseline and 3 months after the beginning of treatment. RESULTS After 3 months, in patients of the intervention group, there was a statistically significant decrease in levels ofd-dimer and mean platelet volume (MPV) but no significant change in neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio. CONCLUSIONS Our results showed that a 3-month treatment with 10 mg rosuvastatin daily can significantly decrease the plasma levels ofd-dimer and MPV, which would support a potential role of statins to reduce activated systemic inflammation among VTE patients. Such effects can be used to reduce the rate of recurrent VTE in these patients.