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Article ; Online: Effect of genetic factors on the response to vitamin D

Slow, Sandy / Pearson, John P / Florkowski, Christopher M / Elder, Peter A / Lewis, John G / Kennedy, Martin A / Murdoch, David R

Nutrition (Burbank, Los Angeles County, Calif.)

2020 Volume 75-76, Page(s) 110761

Abstract: Objectives: Supplementation provides the best means of improving vitamin D status ... single nucleotide polymorphisms (SNPs) in six key vitamin D pathway genes (GC, DHCR7, CYP2 R1, CYP24 A1, CYP27 B1, VDR) were ... vitamin D, n = 153 placebo) were part of VIDARIS (Vitamin D and Acute Respiratory Infections ...

Abstract	Objectives: Supplementation provides the best means of improving vitamin D status; however, individual responses vary partly owing to genetics. The aim of this study was to determine whether 28 single nucleotide polymorphisms (SNPs) in six key vitamin D pathway genes (GC, DHCR7, CYP2 R1, CYP24 A1, CYP27 B1, VDR) were associated with differences in response to supplementation. Methods: Participants (N = 313; n = 160 vitamin D, n = 153 placebo) were part of VIDARIS (Vitamin D and Acute Respiratory Infections Study), a double-blind, randomized controlled trial involving oral monthly supplementation of either vitamin D Results: SNPs within GC, CYP2 R1, and CYP27 B1 were associated with 25(OH)D concentrations following supplementation. However, only two GC gene SNPs (rs2282679, rs1155563) were significant after adjustment for multiple testing. This effect disappeared after more than 2 mo of supplementation. None of the SNPs were significantly associated with Gc-globulin concentrations; however, there was a significant interaction with one SNP in DHCR7 (rs12785878), which was associated with reduced free 25(OH)D concentrations in the supplemented arm. Conclusion: Only variants of GC were associated with 25(OH)D concentrations after supplementation. This effect was modest and disappeared after >2 mo of supplementation, suggesting it may be time/dose-dependent and saturable.
MeSH term(s)	Cholecalciferol ; Dietary Supplements ; Double-Blind Method ; Humans ; Vitamin D ; Vitamin D Deficiency/drug therapy ; Vitamin D Deficiency/genetics ; Vitamin D-Binding Protein/genetics
Chemical Substances	Vitamin D-Binding Protein ; Vitamin D (1406-16-2) ; Cholecalciferol (1C6V77QF41)
Language	English
Publishing date	2020-02-12
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial
ZDB-ID	639259-3
ISSN	1873-1244 ; 0899-9007
ISSN (online)	1873-1244
ISSN	0899-9007
DOI	10.1016/j.nut.2020.110761
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Article ; Online: Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials.

Jolliffe, David A / Camargo, Carlos A / Sluyter, John D / Aglipay, Mary / Aloia, John F / Ganmaa, Davaasambuu / Bergman, Peter / Bischoff-Ferrari, Heike A / Borzutzky, Arturo / Damsgaard, Camilla T / Dubnov-Raz, Gal / Esposito, Susanna / Gilham, Clare / Ginde, Adit A / Golan-Tripto, Inbal / Goodall, Emma C / Grant, Cameron C / Griffiths, Christopher J / Hibbs, Anna Maria /

The lancet. Diabetes & endocrinology

2021 Volume 9, Issue 5, Page(s) 276–292

Abstract: Background: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D ... of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs ... registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D ...

Abstract	Background: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis. Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D Findings: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I Interpretation: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation. Funding: None.
MeSH term(s)	Dietary Supplements ; Humans ; Randomized Controlled Trials as Topic ; Respiratory Tract Infections/diet therapy ; Respiratory Tract Infections/prevention & control ; Treatment Outcome ; Vitamin D/administration & dosage
Chemical Substances	Vitamin D (1406-16-2)
Language	English
Publishing date	2021-03-30
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't ; Systematic Review
ISSN	2213-8595
ISSN (online)	2213-8595
DOI	10.1016/S2213-8587(21)00051-6
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Article ; Online: Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.

Martineau, Adrian R / Jolliffe, David A / Greenberg, Lauren / Aloia, John F / Bergman, Peter / Dubnov-Raz, Gal / Esposito, Susanna / Ganmaa, Davaasambuu / Ginde, Adit A / Goodall, Emma C / Grant, Cameron C / Janssens, Wim / Jensen, Megan E / Kerley, Conor P / Laaksi, Ilkka / Manaseki-Holland, Semira / Mauger, David / Murdoch, David R / Neale, Rachel /

Rees, Judy R / Simpson, Steve / Stelmach, Iwona / Trilok Kumar, Geeta / Urashima, Mitsuyoshi / Camargo, Carlos A / Griffiths, Christopher J / Hooper, Richard L

Health technology assessment (Winchester, England)

2019 Volume 23, Issue 2, Page(s) 1–44

Abstract: Background: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent ... the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and ... trials of supplementation with vitamin D: Study appraisal: Study quality was assessed using ...

Abstract	Background: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity. Objectives: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect. Data sources: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry. Study selection: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D Study appraisal: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity. Results: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity Limitations: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately. Conclusions: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes. Study registration: This study is registered as PROSPERO CRD42014013953. Funding: The National Institute for Health Research Health Technology Assessment programme.
MeSH term(s)	Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Body Mass Index ; Child ; Child, Preschool ; Cholecalciferol/administration & dosage ; Comorbidity ; Dietary Supplements ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Administration Schedule ; Ergocalciferols/administration & dosage ; Female ; Humans ; Infant ; Influenza Vaccines/administration & dosage ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; Respiratory Tract Infections/prevention & control ; Vitamin D/administration & dosage ; Vitamin D/therapeutic use ; Vitamin D Deficiency/drug therapy ; Young Adult
Chemical Substances	Ergocalciferols ; Influenza Vaccines ; Vitamin D (1406-16-2) ; Cholecalciferol (1C6V77QF41)
Language	English
Publishing date	2019-01-23
Publishing country	England
Document type	Meta-Analysis
ZDB-ID	2006765-3
ISSN	2046-4924 ; 1366-5278
ISSN (online)	2046-4924
ISSN	1366-5278
DOI	10.3310/hta23020
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Article: Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials.

Jolliffe, David A / Camargo, Carlos A / Sluyter, John D / Aglipay, Mary / Aloia, John F / Ganmaa, Davaasambuu / Bergman, Peter / Borzutzky, Arturo / Damsgaard, Camilla T / Dubnov-Raz, Gal / Esposito, Susanna / Gilham, Clare / Ginde, Adit A / Golan-Tripto, Inbal / Goodall, Emma C / Grant, Cameron C / Griffiths, Christopher J / Hibbs, Anna Maria / Janssens, Wim /

medRxiv : the preprint server for health sciences

2020

Abstract: Background: A 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D ... of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects ... model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk ...

Abstract	Background: A 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory infections revealed a protective effect of the intervention. Since then, 20 new RCTs have been completed. Methods: Systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from inception to 1st May 2020. Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration, were obtained from study authors. The study was registered with PROSPERO (no. CRD42020190633). Findings: We identified 45 eligible RCTs (total 73,384 participants). Data were obtained for 46,331 (98.0%) of 47,262 participants in 42 studies, aged 0 to 95 years. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.91, 95% CI 0.84 to 0.99; P for heterogeneity 0.01). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of ≤12 months (OR 0.82, 95% CI 0.72 to 0.93). No significant interaction was seen between allocation to vitamin D vs. placebo and dose frequency, dose size, or study duration. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI 0.86 to 1.09). Risk of bias within individual studies was assessed as being low for all but three trials. A funnel plot showed left-sided asymmetry (P=0.008, Egger's test). Interpretation: Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation. Funding: None.
Language	English
Publishing date	2020-11-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.07.14.20152728
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Article ; Online: Effect of adjunctive single high-dose vitamin D

Slow, Sandy / Epton, Michael / Storer, Malina / Thiessen, Rennae / Lim, Steven / Wong, James / Chin, Paul / Tovaranonte, Pleayo / Pearson, John / Chambers, Stephen T / Murdoch, David R

Scientific reports

2018 Volume 8, Issue 1, Page(s) 13829

Abstract: Low vitamin D status is associated with increased risk of pneumonia, greater disease severity and ... poorer outcome. However, no trials have examined the effect of adjunctive vitamin D therapy on outcomes ... controlled trial examining the effects of adjunctive vitamin D in adults hospitalised with CAP. Participants ...

Abstract	Low vitamin D status is associated with increased risk of pneumonia, greater disease severity and poorer outcome. However, no trials have examined the effect of adjunctive vitamin D therapy on outcomes in adults with community-acquired pneumonia (CAP). We conducted a randomised, double-blind, placebo-controlled trial examining the effects of adjunctive vitamin D in adults hospitalised with CAP. Participants were randomised to either a single oral dose of 200,000 IU vitamin D
MeSH term(s)	Adult ; Aged ; Cholecalciferol/administration & dosage ; Cholecalciferol/metabolism ; Cholecalciferol/therapeutic use ; Community-Acquired Infections/drug therapy ; Dietary Supplements ; Double-Blind Method ; Female ; Humans ; Length of Stay ; Male ; Middle Aged ; New Zealand ; Placebo Effect ; Pneumonia/drug therapy ; Vitamin D/administration & dosage ; Vitamin D/metabolism ; Vitamin D/therapeutic use ; Vitamin D Deficiency/drug therapy ; Vitamins/administration & dosage
Chemical Substances	Vitamins ; Vitamin D (1406-16-2) ; Cholecalciferol (1C6V77QF41)
Language	English
Publishing date	2018-09-14
Publishing country	England
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-32162-2
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Article ; Online: Digital psychosocial intervention for depression among older adults in socioeconomically deprived areas in Brazil (PRODIGITAL-D): protocol for an individually randomised controlled trial.

Nakamura, Carina Akemi / Scazufca, Marcia / Moretti, Felipe Azevedo / Didone, Thiago Vinicius Nadaleto / de Sá Martins, Mariana Mendes / Pereira, Luara Aragoni / de Souza, Caio Hudson Queiroz / de Oliveira, Gabriel Macias / da Costa, Marcelo Oliveira / Machado, Marcelo / da Silva Bitencourt, Evelyn / Dos Santos, Monica Souza / Murdoch, Jamie / van de Ven, Pepijn / Seward, Nadine / Hollingworth, William / Peters, Tim J / Araya, Ricardo

Trials

2022 Volume 23, Issue 1, Page(s) 761

Abstract: Background: Depression in older adults is a challenge for health systems in most low- and middle-income countries (LMICs). Digital strategies for the management of this condition have been emerging worldwide, but the effectiveness of most of them is ... ...

Abstract	Background: Depression in older adults is a challenge for health systems in most low- and middle-income countries (LMICs). Digital strategies for the management of this condition have been emerging worldwide, but the effectiveness of most of them is still unclear, especially among older adults. Thus, we aim to assess the effectiveness and cost-effectiveness of a digital psychosocial intervention to treat depression among older adults living in socioeconomically deprived areas in Guarulhos, Brazil. Methods: We will conduct a two-arm individually randomised controlled trial with 1:1 allocation ratio. Five hundred older adults aged 60 years or over with depressive symptomatology (9-item Patient Health Questionnaire score, PHQ-9 ≥ 10) and registered with one of the primary care clinics will be recruited to participate in this study. A 6-week digital psychosocial programme, named Viva Vida, will be delivered via WhatsApp to participants allocated to the intervention arm. The Viva Vida will send psychoeducational and behavioural activation audio and visual messages 4 days a week for 6 weeks. The control arm will only receive a single message with general information about depression. The primary outcome will be the proportion of depression recovery (PHQ-9 < 10) assessed at 3 months. The cost-effectiveness of the intervention will be assessed at 5 months. A detailed process evaluation will be used to explore context and important implementation outcomes. Discussion: This programme was based on the PROACTIVE intervention and designed to be delivered without face-to-face contact. If effective, it could be a simple treatment option, appropriate not only when social distancing is required, but it could also be included as a regular public health programme to initiate depression treatment, particularly in LMICs where resources allocated to mental health are scarce. Trial registration: Registro Brasileiro de Ensaios Clínicos (ReBEC), RBR-4c94dtn. Registered on 22 October 2021 (submitted on 03 August 2021).
MeSH term(s)	Aged ; Brazil ; Depression/diagnosis ; Depression/psychology ; Depression/therapy ; Humans ; Mental Health ; Psychosocial Intervention ; Randomized Controlled Trials as Topic ; Treatment Outcome
Language	English
Publishing date	2022-09-07
Publishing country	England
Document type	Clinical Trial Protocol ; Journal Article
ZDB-ID	2040523-6
ISSN	1745-6215 ; 1468-6694 ; 1745-6215
ISSN (online)	1745-6215
ISSN	1468-6694 ; 1745-6215
DOI	10.1186/s13063-022-06623-z
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Article ; Online: Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.

Martineau, Adrian R / Jolliffe, David A / Hooper, Richard L / Greenberg, Lauren / Aloia, John F / Bergman, Peter / Dubnov-Raz, Gal / Esposito, Susanna / Ganmaa, Davaasambuu / Ginde, Adit A / Goodall, Emma C / Grant, Cameron C / Griffiths, Christopher J / Janssens, Wim / Laaksi, Ilkka / Manaseki-Holland, Semira / Mauger, David / Murdoch, David R / Neale, Rachel /

Rees, Judy R / Simpson, Steve / Stelmach, Iwona / Kumar, Geeta Trilok / Urashima, Mitsuyoshi / Camargo, Carlos A

BMJ (Clinical research ed.)

2017 Volume 356, Page(s) i6583

Abstract: ... ...

Abstract	Objectives
MeSH term(s)	Dietary Supplements/adverse effects ; Humans ; Randomized Controlled Trials as Topic ; Respiratory Tract Infections/diet therapy ; Respiratory Tract Infections/prevention & control ; Vitamin D/administration & dosage ; Vitamin D/adverse effects
Chemical Substances	Vitamin D (1406-16-2)
Language	English
Publishing date	2017-02-15
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Review ; Systematic Review
ZDB-ID	1362901-3
ISSN	1756-1833 ; 0959-8154 ; 0959-8146 ; 0959-8138 ; 0959-535X ; 1759-2151
ISSN (online)	1756-1833
ISSN	0959-8154 ; 0959-8146 ; 0959-8138 ; 0959-535X ; 1759-2151
DOI	10.1136/bmj.i6583
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Article ; Online: Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials

Jolliffe, D. / Camargo, C. A. / Sluyter, J. / Aglipay, M. / Aloia, J. / Bergman, P. / Damsgaard, C. / Dubnov-Raz, G. / Esposito, S. / Ganmaa, D. / Gilham, C. / Ginde, A. / Grant, C. / Griffiths, C. / Hibbs, A. M. / Janssens, W. / Khadilkar, A. V. / Laaksi, I. / Lee, M. T. /

Loeb, M. / Maguire, J. / Mauger, D. T. / Majak, P. / Manaseki-Holland, S. / Murdoch, D. / Nakashima, A. / Neale, R. E. / Rake, C. / Rees, J. / Rosendahl, J. / Scragg, R. / Shah, D. / Shimizu, Y. / Simpson-Yap, S. / Trilok Kumar, G. / Urashima, M. / Martineau, A. R.

Abstract: Objectives: To assess the overall effect of vitamin D supplementation on risk of acute ... meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random ... effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D ...

Abstract	Objectives: To assess the overall effect of vitamin D supplementation on risk of acute respiratory infection (ARI), and to identify factors modifying this effect. Design: We conducted a systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. Data Sources: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard RCT Number (ISRCTN) registry from inception to May 2020. Eligibility Criteria for Selecting Studies: Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Results: We identified 40 eligible RCTs (total 30,956 participants, aged 0 to 95 years). Data were obtained for 29,841 (96.5%) of 30,909 participants in 39 studies. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.89, 95% CI 0.81 to 0.98; P for heterogeneity 0.009). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of [≤]12 months (OR 0.82, 95% CI 0.72 to 0.94). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.94, 95% CI 0.81 to 1.08). Risk of bias within individual studies was assessed as being low for all but two trials. A funnel plot showed asymmetry, suggesting that small trials showing non-protective effects of vitamin D may have been omitted from the meta-analysis. Conclusions: Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. The overall effect size may have been over-estimated due to publication bias. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation.
Keywords	covid19
Publisher	MedRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.07.14.20152728
Database	COVID19

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Article ; Online: DISC1 regulates N-methyl-D-aspartate receptor dynamics: abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness.

Malavasi, Elise L V / Economides, Kyriakos D / Grünewald, Ellen / Makedonopoulou, Paraskevi / Gautier, Philippe / Mackie, Shaun / Murphy, Laura C / Murdoch, Hannah / Crummie, Darragh / Ogawa, Fumiaki / McCartney, Daniel L / O'Sullivan, Shane T / Burr, Karen / Torrance, Helen S / Phillips, Jonathan / Bonneau, Marion / Anderson, Susan M / Perry, Paul / Pearson, Matthew /

Constantinides, Costas / Davidson-Smith, Hazel / Kabiri, Mostafa / Duff, Barbara / Johnstone, Mandy / Polites, H Greg / Lawrie, Stephen M / Blackwood, Douglas H / Semple, Colin A / Evans, Kathryn L / Didier, Michel / Chandran, Siddharthan / McIntosh, Andrew M / Price, David J / Houslay, Miles D / Porteous, David J / Millar, J Kirsty

Translational psychiatry

2018 Volume 8, Issue 1, Page(s) 184

Abstract: ... understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition ...

Abstract	The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of the translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether, our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.
MeSH term(s)	Adaptor Proteins, Vesicular Transport ; Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Genome-Wide Association Study ; Humans ; Mice ; Models, Animal ; Mood Disorders/genetics ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neuronal Plasticity ; Neurons/metabolism ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/metabolism ; Schizophrenia/genetics ; Sequence Analysis, RNA ; Synapses/metabolism ; Translocation, Genetic
Chemical Substances	Adaptor Proteins, Vesicular Transport ; Carrier Proteins ; Disc1 protein, mouse ; Gprin1 protein, mouse ; NR2B NMDA receptor ; Nerve Tissue Proteins ; Receptors, N-Methyl-D-Aspartate ; Trak1 protein, mouse
Language	English
Publishing date	2018-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-018-0228-1
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Article ; Online: Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials

Jolliffe, David / Camargo, Carlos A / Sluyter, John / Aglipay, Mary / Aloia, John / Bergman, Peter / Damsgaard, Camilla / Dubnov-Raz, Gal / Esposito, Susanna / Ganmaa, Davaasambuu / Gilham, Clare / Ginde, Adit / Grant, Cameron / Griffiths, Chris / Hibbs, Anna Maria / Janssens, Wim / Khadilkar, Anuradha Vaman / Laaksi, Ilkka / Lee, Margaret T /

Loeb, Mark / Maguire, Jonathon / Mauger, David T / Majak, Pawel / Manaseki-Holland, Semira / Murdoch, David / Nakashima, Akio / Neale, Rachel E / Rake, Christine / Rees, Judith / Rosendahl, Jenni / Scragg, Robert / Shah, Dheeraj / Shimizu, Yoshiki / Simpson-Yap, Steve / Trilok Kumar, Geeta / Urashima, Mitsuyoshi / Martineau, Adrian R

medRxiv

Abstract	Objectives: To assess the overall effect of vitamin D supplementation on risk of acute respiratory infection (ARI), and to identify factors modifying this effect. Design: We conducted a systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. Data Sources: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard RCT Number (ISRCTN) registry from inception to May 2020. Eligibility Criteria for Selecting Studies: Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Results: We identified 40 eligible RCTs (total 30,956 participants, aged 0 to 95 years). Data were obtained for 29,841 (96.5%) of 30,909 participants in 39 studies. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.89, 95% CI 0.81 to 0.98; P for heterogeneity 0.009). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of ≤12 months (OR 0.82, 95% CI 0.72 to 0.94). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.94, 95% CI 0.81 to 1.08). Risk of bias within individual studies was assessed as being low for all but two trials. A funnel plot showed asymmetry, suggesting that small trials showing non-protective effects of vitamin D may have been omitted from the meta-analysis. Conclusions: Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. The overall effect size may have been over-estimated due to publication bias. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation.
Keywords	covid19
Language	English
Publishing date	2020-07-17
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.07.14.20152728
Database	COVID19

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