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1.
Additional effect of perioperative, compared with preoperative, immunonutrition after pancreaticoduodenectomy: A randomized, controlled trial.
Miyauchi, Y, Furukawa, K, Suzuki, D, Yoshitomi, H, Takayashiki, T, Kuboki, S, Miyazaki, M, Ohtsuka, M
International journal of surgery (London, England). 2019;:69-75
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Abstract
BACKGROUND We have reported that perioperative and preoperative immunonutrition reduced infectious complications in patients undergoing pancreaticoduodenectomy; however, it is unclear whether perioperative immunonutrition has additional effects compared with preoperative immunonutrition. The present study evaluated whether perioperative, compared with preoperative, immunonutrition has additional effects on cell-mediated immunity and the infection rate after pancreaticoduodenectomy. MATERIALS AND METHODS This was a prospective, randomized clinical trial conducted in our institution. Oral supplementation enriched with arginine, ω-3 fatty acids, and dietary nucleotides was given by enteral infusion to 30 patients before and after surgery (perioperative group); 30 patients received the same enriched formula before surgery and standard enteral nutrition following surgery (preoperative group). The primary endpoint was concanavalin (Con A)- or phytohemagglutinin (PHA)-stimulated lymphocyte proliferation on postoperative day (POD) 7, which is an index of cell-mediated immunity; the secondary endpoint was the postoperative infection rate. RESULTS There were no significant differences in Con A- or PHA-stimulated lymphocyte proliferation on POD 7 between the groups. There was no significant difference in the postoperative infection rate between the two groups. In the post hoc subgroup analysis, with respect to the effect on the infection rate, a significant interaction was found only between a long operative time and perioperative immunonutrition. CONCLUSIONS There were no additional effects of perioperative, compared with preoperative, immunonutrition on postoperative immunity and infectious complications in patients undergoing pancreaticoduodenectomy.
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Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon β-1a.
Hupperts, R, Smolders, J, Vieth, R, Holmøy, T, Marhardt, K, Schluep, M, Killestein, J, Barkhof, F, Beelke, M, Grimaldi, LME, et al
Neurology. 2019;(20):e1906-e1916
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Abstract
OBJECTIVE In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS. METHODS Eligible patients with RRMS treated with SC interferon-β-1a (IFN-β-1a) 44 μg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-β-1a plus placebo (n = 116) or SC IFN-β-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. RESULTS At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035). CONCLUSIONS SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-β-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS. CLINICALTRIALSGOV IDENTIFIER NCT01285401. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that for patients with RRMS treated with SC IFN-β-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.
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Broncho-vaxom alleviates persistent allergic rhinitis in patients by improving Th1/Th2 cytokine balance of nasal mucosa.
Meng, Q, Li, P, Li, Y, Chen, J, Wang, L, He, L, Xie, J, Gao, X
Rhinology. 2019;(6):451-459
Abstract
BACKGROUND Probiotics are mainly distributed in the mucosal system and have the ability to enhance mucosal barrier function and regulate immune responses. Broncho-Vaxom (BV), as a probiotic, has been applied to patients suffering from respiratory tract infections, but its potential effectiveness in allergic rhinitis (AR) has not been evaluated in human. This study aimed to investigate the clinical efficacy of BV in patients with persistent AR and to elucidate the underlying cellular mechanisms. METHODS Sixty patients with AR were enrolled to this study and were randomly assigned to the BV group (n=30) and the placebo group (n=30). Changes of clinical symptoms and laboratory parameters of allergic inflammation were measured at baseline visit, immediately after BV treatment, four weeks, and eight weeks after the BV treatment. RESULTS After BV treatment, medication score in the BV group was significantly decreased compared with placebo group, along with a significant drop of the total nasal symptom score and the individual nasal symptom scores (itching score: 23.72±5.32%; nasal rhinorrhea score: 18.59±4.83%; sneezing score: 23.08±4.98%). The levels of IL-4 and IL-13 in nasal lavage were diminished remarkably while the level of INF-γ was markedly increased in the BV group. This rendered a significant reduction of the ratio of IL-4/INF-γ. Moreover, a decrease of eosinophils in nasal smear was observed after BV treatment. The BV-induced favorable changes sustained for at least four to eight weeks post BV treatment. CONCLUSION Oral administration of BV offers remarkable and sustained efficacy in alleviating AR symptoms and may be considered as an alternative therapeutic strategy for patients with persistent AR. BV acts by improving the overall mucosal immunity via restoring and maintaining the normal Th1/Th2 cytokine balance as an underlying cellular/signaling mechanism.
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Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): A phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine.
Gonzalez-Lopez, A, Oostendorp, J, Koernicke, T, Fadini, T, D'Oro, U, Baker, S, O'Hagan, DT, Del Giudice, G, Siena, E, Finco, O, et al
Clinical immunology (Orlando, Fla.). 2019;:108275
Abstract
An adjuvant system (AS37) has been developed containing a synthetic toll-like receptor agonist (TLR7a). We conducted a phase I randomized, observer-blind, dose-escalation study to assess the safety and immunogenicity of an investigational AS37-adjuvanted meningococcus C (MenC) conjugate vaccine in healthy adults (NCT02639351). A control group received a licensed MenC conjugate alum-adjuvanted vaccine. Eighty participants were randomized to receive one dose of control or investigational vaccine containing AS37 (TLR7a dose 12.5, 25, 50, 100 μg). All vaccines were well tolerated, apart from in the TLR7a 100 μg dose group, which had three reports (18.8%) of severe systemic adverse events. Four weeks after vaccination, human complement serum bactericidal assay seroresponse rates against MenC were 56-81% in all groups, and ELISA seroresponses were ≥81% for all AS37-adjuvanted vaccine groups (100% in 50 and 100 μg dose groups) and 88% in the control group. Antibody responses were maintained at six months after vaccination.
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Fatty acids as essential adjuvants to treat various ailments and their role in drug delivery: A review.
Katdare, A, Thakkar, S, Dhepale, S, Khunt, D, Misra, M
Nutrition (Burbank, Los Angeles County, Calif.). 2019;:138-157
Abstract
Since the discovery of fatty acids, a niche has been carved for their vital role as adjuvants in drug delivery and as treatment for various diseases. The literature has repeatedly described the essential role of various fatty acids in treating a wide range of diseases and disorders, from central nervous system diseases to wound healing. The use of fatty acids has expanded to many horizons and in recent decades they have gained importance as drug delivery adjuvants in addition to their auxiliary benefits in treating various diseases. Although fatty acids aid in solving both formulation-based and therapeutic challenges to our knowledge, they have never been viewed as dual agents in modern scientific literature. The aim of this review was to provide this perspective and combine the very discreet literature about fatty acids, which includes their role as therapeutic adjuvants and drug delivery agents. It gives insights on the use of fatty acids in treating the diseases of the eye, skin, central nervous system, viral diseases, and so on. The review further discusses how the structure of fatty acids plays an important role in therapeutic activity and affects formulation stability.
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Flagellin/NLRC4 Pathway Rescues NLRP3-Inflammasome Defect in Dendritic Cells From HIV-Infected Patients: Perspective for New Adjuvant in Immunocompromised Individuals.
Dos Reis, EC, Leal, VNC, Soares, JLDS, Fernandes, FP, Souza de Lima, D, de Alencar, BC, Pontillo, A
Frontiers in immunology. 2019;:1291
Abstract
Introduction: NLRP3 inflammasome plays a key role in dendritic cells (DC) activation in response to vaccine adjuvants, however we previously showed that it is not properly activated in DC from HIV-infected patients (HIV-DC), explaining, at least in part, the poor response to immunization of these patients. Taking in account that several cytoplasmic receptors are able to activate inflammasome, and that bacterial components are considered as a novel and efficient adjuvant, we postulated that bacterial flagellin (FLG), a natural ligand of NAIP/NLRC4 inflammasome, could rescue the activation of the complex in HIV-DC. Objective: Demonstrate that FLG is able to activate monocyte-derived dendritic cells from HIV-infected individuals better than LPS, and to what extent the entity of inflammasome activation differs between DC from HIV-infected patients and healthy donors. Methods: Monocyte-derived dendritic cells from HIV-infected patients (HIV-DC) and healthy donors (HD-DC) were stimulated with FLG, and inflammasome as well as DC activation (phenotypic profile, cytokine production, autologous lymphocytes activation) were compared. Chemical and genetic inhibitors were used to depict the relative contribution of NLRC4 and NLRP3 in HIV/HD-DC response to FLG. Results: FLG properly activates HD-DC and HIV-DC. FLG induces higher inflammasome activation than LPS in HIV-DC. FLG acts through NLRC4 and NLRP3 in HD-DC, but at a lesser extent in HIV-DC due to intrinsic NLRP3 defect. Conclusions: FLG by-passes NLRP3 defect in HIV-DC, through the activation of NAIP/NLRC4 inflammasome, indicating possible future use of the bacterial component as an efficient adjuvant in immunocompromised individuals.
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Safety and immunogenicity of the chlamydia vaccine candidate CTH522 adjuvanted with CAF01 liposomes or aluminium hydroxide: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial.
Abraham, S, Juel, HB, Bang, P, Cheeseman, HM, Dohn, RB, Cole, T, Kristiansen, MP, Korsholm, KS, Lewis, D, Olsen, AW, et al
The Lancet. Infectious diseases. 2019;(10):1091-1100
Abstract
BACKGROUND Chlamydia is the most common sexually transmitted bacterial infection worldwide. National screening programmes and antibiotic treatment have failed to decrease incidence, and to date no vaccines against genital chlamydia have been tested in clinical trials. We aimed to assess the safety and immunogenicity, in humans, of a novel chlamydia vaccine based on a recombinant protein subunit (CTH522) in a prime-boost immunisation schedule. METHODS This phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial was done at Hammersmith Hospital in London, UK, in healthy women aged 19-45 years. Participants were randomly assigned (3:3:1) to three groups: CTH522 adjuvanted with CAF01 liposomes (CTH522:CAF01), CTH522 adjuvanted with aluminium hydroxide (CTH522:AH), or placebo (saline). Participants received three intramuscular injections of 85 μg vaccine (with adjuvant) or placebo to the deltoid region of the arm at 0, 1, and 4 months, followed by two intranasal administrations of 30 μg unadjuvanted vaccine or placebo (one in each nostril) at months 4·5 and 5·0. The primary outcome was safety and the secondary outcome was humoral immunogenicity (anti-CTH522 IgG seroconversion). This study is registered with Clinicaltrials.gov, number NCT02787109. FINDINGS Between Aug 15, 2016, and Feb 13, 2017, 35 women were randomly assigned (15 to CTH522:CAF01, 15 to CTH522:AH, and five to placebo). 32 (91%) received all five vaccinations and all participants were included in the intention-to-treat analyses. No related serious adverse reactions were reported, and the most frequent adverse events were mild local injection-site reactions, which were reported in all (15 [100%] of 15) participants in the two vaccine groups and in three (60%) of five participants in the placebo group (p=0·0526 for both comparisons). Intranasal vaccination was not associated with a higher frequency of related local reactions (reported in seven [47%] of 15 participants in the active treatment groups vs three [60%] of five in the placebo group; p=1·000). Both CTH522:CAF01 and CTH522:AH induced anti-CTH522 IgG seroconversion in 15 (100%) of 15 participants after five immunisations, whereas no participants in the placebo group seroconverted. CTH522:CAF01 showed accelerated seroconversion, increased IgG titres, an enhanced mucosal antibody profile, and a more consistent cell-mediated immune response profile compared with CTH522:AH. INTERPRETATION CTH522 adjuvanted with either CAF01 or aluminium hydroxide appears to be safe and well tolerated. Both vaccines were immunogenic, although CTH522:CAF01 had a better immunogenicity profile, holding promise for further clinical development. FUNDING European Commission and The Innovation Fund Denmark.
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Effects of pidotimod and bifidobacteria mixture on clinical symptoms and urinary metabolomic profile of children with recurrent respiratory infections: a randomized placebo-controlled trial.
Santamaria, F, Montella, S, Stocchero, M, Pirillo, P, Bozzetto, S, Giordano, G, Poeta, M, Baraldi, E
Pulmonary pharmacology & therapeutics. 2019;:101818
Abstract
BACKGROUND Many preschool children develop recurrent respiratory tract infections (RRI). Strategies to prevent RRI include the use of immunomodulators as pidotimod or probiotics, but there is limited evidence of their efficacy on clinical features or on urine metabolic profile. OBJECTIVE To evaluate whether pidotimod and/or bifidobacteria can reduce RRI morbidity and influence the urine metabolic profile in preschool children. MATERIALS AND METHODS Children aged 3-6 years with RRI were enrolled in a four-arm, exploratory, prospective, randomized, double-blinded, placebo-controlled trial. Patients were randomly assigned to receive pidotimod plus bifidobacteria, pidotimod plus placebo, bifidobacteria plus placebo or double placebo for the first 10 days of each month over 4 consecutive months. Respiratory symptoms and infections were recorded with a daily diary by parents during the study. Metabolomic analyses on urine samples collected before and after treatment were performed. RESULTS Compared to placebo, children receiving pidotimod, alone or with bifidobacteria, had more symptom-free days (69 versus 44, p = 0.003; and 65 versus 44, p = 0.02, respectively) and a lower percentage of days with common cold (17% versus 37%, p = 0.005; and 15% versus 37%, p = 0.004, respectively). The metabolomic analysis showed that children treated with Pidotimod (alone or in combination with bifidobacteria) present, respect to children treated with placebo, a biochemical profile characterized by compounds related to the pathway of steroids hormones, hippuric acid and tryptophan. No significant difference in the metabolic profile was found between children receiving bifidobacteria alone and controls. CONCLUSIONS Preschool children with RRI treated with pidotimod have better clinical outcomes and a different urine metabolomic profile than subjects receiving placebo. Further investigations are needed to clarify the connection between pidotimod and gut microbiome.
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Reuterinos® as adjuvant for peri-implant treatment: A pilot study.
Lauritano, D, Carinci, F, Palmieri, A, Cura, F, Caruso, S, Candotto, V
International journal of immunopathology and pharmacology. 2019;:2058738419827745
Abstract
The objective of this study was to evaluate the effects of lozenges-containing Lactobacillus reuteri as an adjuvant treatment of peri-implant mucositis and to detect the level of L. reuteri colonization in the peri-implant tissues of treated patients. A total of 10 patients were selected. Subjects with at least one implant affected by peri-implant mucositis, with gingival index (GI) of ⩾2 in each quadrant, evaluated at the buccal aspect of all teeth. Patients included in the study were partially edentulous and had implants with mucositis or peri-implantitis. Implants with radiographic bone loss of ⩾5 mm and/or ⩾50% of the implant length were excluded, and only one implant per patient was included. Each patient received L. reuteri-containing lozenges. Microbiological sampling was performed at baseline and on day 28 and analysed by polymerase chain reaction (PCR). Our results indicate that the use of the probiotic did not influence the peri-implant microbiota in a statistically significant way, although there was a reduction in the number of periodontal and peri-implant species. The lack of statistically significant microbiological changes could be explained either by the small sample population or by the short evaluation period. Therefore, the poor colonization of L. reuteri in the peri-implant pockets can be explained by the different anatomical and histological characteristics of the interface of the dental-gingival unit with respect to the periodontal sulcus. The administration of a daily lozenge of L. reuteri for 4 weeks had a limited effect on the microbiological analysis. Probiotics provide an alternative therapeutic approach to consider in the prevention and treatment of peri-implant diseases, but further long-term prospective studies with standardized variables are needed.
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Systemic treatments for alopecia areata: A systematic review.
Lai, VWY, Chen, G, Gin, D, Sinclair, R
The Australasian journal of dermatology. 2019;(1):e1-e13
Abstract
A range of systemic treatments are used for alopecia areata with variable evidence supporting efficacy. In this systematic review, we evaluated the evidence surrounding systemic treatments for alopecia areata, alopecia totalis and alopecia universalis. A systematic search was conducted of the peer-reviewed literature published between 1946 and March 2018 via Medline, Embase, Amed, the Cochrane Central Register of Controlled Trials, PsychINFO and Lilacs. All randomised controlled trials (RCTs) that evaluated the effectiveness of systemic treatments for individuals with alopecia areata, totalis or universalis were included. Sixteen studies were included with a total of 768 participants. We found eight placebo-controlled RCTs, three RCTs comparing two systemic treatments and five RCTs comparing three treatments. A total of 15 different systemic therapies were investigated. The most frequently investigated therapy was oral prednisolone pulse therapy and oral inosiplex. There was significant variability in the definition of treatment success. No study evaluated the impact of pharmacotherapy on quality of life using complete quantitative quality of life instruments. Adverse events were reported in 13 studies and were corticosteroid related or otherwise well tolerated. Relapse rates were considerable in the four studies that reported this outcome. There is currently no specific systemic therapy that is supported by robust body of evidence from RCTs. The current evidence suggests efficacy of oral prednisolone pulse therapy and oral inosiplex. Evidence does not support the use of oral zinc sulphate, alefacept and efalizumab. Future RCTs should be adequately powered and employ clearly defined clinical response endpoints to allow future meta-analyses.