Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and ...meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.
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BFBNIB, CMK, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The conformational change of a host protein, PrPC, into a disease-associated isoform, PrPSc, appears to play a critical role in the pathogenesis of prion diseases such as Creutzfeldt-Jakob disease ...and scrapie. However, the fundamental mechanism by which infectious prions are produced in neurons remains unknown. To investigate the mechanism of prion formation biochemically, we conducted a series of experiments using the protein misfolding cyclic amplification (PMCA) technique with a preparation containing only native PrPC and copurified lipid molecules. These experiments showed that successful PMCA propagation of PrPSc molecules in a purified system requires accessory polyanion molecules. In addition, we found that PrPSc molecules could be formed de novo from these defined components in the absence of preexisting prions. Inoculation of samples containing either prion-seeded or spontaneously generated PrPSc molecules into hamsters caused scrapie, which was transmissible on second passage. These results show that prions able to infect wild-type hamsters can be formed from a minimal set of components including native PrPC molecules, copurified lipid molecules, and a synthetic polyanion.
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Prions containing misfolded prion protein (PrP Sᶜ) can be formed with cofactor molecules using the technique of serial protein misfolding cyclic amplification. However, it remains unknown whether ...cofactors materially participate in maintaining prion conformation and infectious properties. Here we show that withdrawal of cofactor molecules during serial propagation of purified recombinant prions caused adaptation of PrP Sᶜ structure accompanied by a reduction in specific infectivity of >10 ⁵-fold, to undetectable levels, despite the ability of adapted “protein-only” PrP Sᶜ molecules to self-propagate in vitro. We also report that changing only the cofactor component of a minimal reaction substrate mixture during serial propagation induced major changes in the strain properties of an infectious recombinant prion. Moreover, propagation with only one functional cofactor (phosphatidylethanolamine) induced the conversion of three distinct strains into a single strain with unique infectious properties and PrP Sᶜ structure. Taken together, these results indicate that cofactor molecules can regulate the defining features of mammalian prions: PrP Sᶜ conformation, infectivity, and strain properties. These findings suggest that cofactor molecules likely are integral components of infectious prions.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
To characterize the experiences of providers in completing the cause of death section on death certificates, with particular reference to deaths in people who have cancer.
Focus groups were conducted ...until thematic saturation was reached, resulting in four groups over three months. Participants were from a variety of specialties and levels and types of training. Focus groups were recorded and transcribed verbatim and analyzed using constant comparison analysis.
Three types of challenges to case classification were identified. 1) Infrastructural and procedural challenges encountered when completing death certificates, including the rigid structure of the form, lack of training in its completion, and lack of real-time feedback. 2) Clinical uncertainty and the varied approaches providers take to determine the cause of death based on their perception of the purpose of the death certificate. 3) Choosing cause of death in decedents with a history of cancer.
There are specific and substantial challenges in the death certification process that lead to errors in documenting the cause of death, but many of these challenges could be addressed with structural change to the forms or mechanism of training. Using these data to inform change could improve the death certification process and reliability of this data.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several studies have shown an increased risk of cancer after non melanoma skin cancers (NMSC) but the individual risk factors underlying this risk have not been elucidated, especially in relation to ...sun exposure and skin sensitivity to sunlight.
The aim of this study was to examine the individual risk factors associated with the development of subsequent cancers after non melanoma skin cancer.
Participants in the population-based New Hampshire Skin Cancer Study provided detailed risk factor data, and subsequent cancers were identified via linkage with the state cancer registry. Deaths were identified via state and national death records. A Cox proportional hazard model was used to estimate risk of subsequent malignancies in NMSC patients versus controls and to assess the potential confounding effects of multiple risk factors on this risk.
Among 3584 participants, risk of a subsequent cancer (other than NMSC) was higher after basal cell carcinoma (BCC) (adjusted HR 1.40 95% CI 1.15, 1.71) than squamous cell carcinoma (SCC) (adjusted HR 1.18 95% CI 0.95, 1.46) compared to controls (adjusted for age, sex and current cigarette smoking). After SCC, risk was higher among those diagnosed before age 60 (HR 1.96 95% CI 1.24, 3.12). An over 3-fold risk of melanoma after SCC (HR 3.62; 95% CI 1.85, 7.11) and BCC (HR 3.28; 95% CI 1.66, 6.51) was observed, even after further adjustment for sun exposure-related factors and family history of skin cancer. In men, prostate cancer incidence was higher after BCC compared to controls (HR 1.64; 95% CI 1.10, 2.46).
Our population-based study indicates an increased cancer risk after NMSC that cannot be fully explained by known cancer risk factors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prion diseases are fatal and infectious neurodegenerative diseases in humans and other mammals caused by templated misfolding of the endogenous prion protein (PrP). Although there is currently no ...vaccine or therapy against prion disease, several classes of small-molecule compounds have been shown to increase disease-free incubation time in prion-infected mice. An apparent obstacle to effective anti-prion therapy is the emergence of drug-resistant strains during static therapy with either single compounds or multi-drug combination regimens. Here, we treated scrapie-infected mice with dynamic regimens that alternate between different classes of anti-prion drugs. The results show that alternating regimens containing various combinations of Anle138b, IND24 and IND116135 reduce the incidence of combination drug resistance, but do not significantly increase long-term disease-free survival compared to monotherapy. Furthermore, the alternating regimens induced regional vacuolation profiles resembling those generated by a single component of the alternating regimen, suggesting the emergence of strain dominance.
Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause ...inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrPSc propagation in vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this placebo-controlled trial involving patients with recently diagnosed adenomas, daily supplementation with vitamin D
3
(1000 IU), calcium (1200 mg), or both did not reduce the risk of recurrent ...colorectal adenomas over 3 to 5 years.
Vitamin D, an essential nutrient that is important for bone mineralization and calcium homeostasis,
1
also has effects beyond bone and calcium. Many studies have shown it to be antineoplastic, particularly in the colorectum. In in vitro studies, vitamin D and its analogues have been shown to inhibit proliferation, induce differentiation, inhibit angiogenesis, and promote apoptosis in epithelial tissues.
2
,
3
High vitamin D intake inhibits experimental carcinogenesis,
2
,
3
even in animals that are vitamin D–replete.
4
Observational studies of vitamin D intake
5
–
7
and serum levels of 25-hydroxyvitamin D
8
–
10
have shown inverse associations between these measures and the risk of colorectal . . .
Background
Late-stage colorectal cancer (CRC) is associated with significantly less effective treatment and poorer survival than early-stage colorectal cancer.
Objective
Identify and assess patient ...characteristics, demographic factors, and lifestyle factors that are associated with late-stage colorectal cancer at diagnosis.
Approach
We linked two longstanding statewide, population-based registry databases: the New Hampshire Colonoscopy Registry and the New Hampshire State Cancer Registry, to assess the associations between patient characteristics and late-stage CRC diagnoses. The State Cancer Registry provided information on cancer stage and the Colonoscopy Registry provided detailed information on patient characteristics and lifestyle factors, allowing these factors to be analyzed in relation to colorectal cancer stage.
Key Results
The risk of late-stage CRC diagnosis was highest among those diagnosed at a young age (< 50 years old) (OR 1.81, 95% CI 1.27–2.58). Those with Medicaid were also at increased risk, particularly < 65 years of age (OR 2.32, 95% CI 1.05–5.26). A family or personal history of polyps and/or CRC was associated with early stage at diagnosis (
p
= 0.014).
Conclusions
Public health outreach and screening efforts should focused on patients at risk of late-stage CRC to encourage earlier diagnosis and prevention. Underserved patients have a lower rate of CRC screening and an increased risk of late-stage CRC, emphasizing the critical need to reach these populations. Further investigation of susceptibility characteristics and the effectiveness of non-invasive early screening techniques is warranted to address the late-stage CRC diagnoses in young individuals.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Context:
Adequate serum 25-hydroxyvitamin D concentrations, 25(OH)D, are required for optimal bone health, and low levels are associated with chronic diseases.
Objective:
We investigated whether 41 ...candidate single nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes (GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR, and CASR) are associated with 25(OH)D or modify the increase in 25(OH)D from vitamin D3 supplementation.
Design and Setting:
Baseline and year 1 25(OH)D measurements from a randomized controlled trial conducted at 11 clinical centers in the United States.
Participants:
A total of 1787 healthy non-Hispanic white participants aged 45–75 years.
Interventions:
Vitamin D3 (1000 IU/d), calcium carbonate (1200 mg/d elemental), both, or placebo.
Main Outcome Measures:
Genotype main effects and interactions with vitamin D3 treatment estimated using multiple linear regression.
Results:
The baseline serum 25(OH)D was 25.4 ± 8.7 ng/mL (mean ± SD). Associations with baseline levels were discovered for SNPs in CYP24A1 (rs2209314, rs2762939) and confirmed for SNPs in GC and CYP2R1. After 1 year, 25(OH)D increased on average by 6.1 ± 8.9 ng/mL on vitamin D3 treatment and decreased by 1.1 ± 8.4 ng/mL on placebo. The increase in 25(OH)D due to vitamin D3 supplementation was modified by genotypes at rs10766197 near CYP2R1, rs6013897 near CYP24A1, and rs7968585 near VDR.
Conclusions:
The increase in 25(OH)D attributable to vitamin D3 supplementation may vary according to common genetic differences in vitamin D 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), and the vitamin D receptor (VDR) genes. These findings have implications for achieving optimal vitamin D status and potentially for vitamin D-related health outcomes.
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