The association between serum vitamin D status and dental caries or molar incisor hypomineralisation in 7-9-year-old Norwegian children: a cross-sectional study.

BACKGROUND: Research focusing on the association between serum vitamin D and oral health outcomes in children, such as dental caries and molar incisor hypomineralisation (MIH), shows inconsistent results. Previous studies have predominantly investigated dental caries and MIH as dichotomized outcomes, which limits the information on their distribution. In addition, the methods used for analysing serum vitamin D have varied. The present study aimed to investigate potential associations between serum vitamin D status measured by Liquid Chromatography with Tandem Mass Spectrometry (LC-MS/MS) and the prevalence, as well as the number of teeth, affected by dental caries or MIH among 7-9-year-old Norwegian children. METHODS: The study had a cross-sectional design and included 101 children aged 7-9 years. Serum 25-hydroxyvitamin D (25(OH)D) was measured and included as continuous (per 25 nmol/l) and categorised (insufficient (< 50 nmol/l) and sufficient (≥50 nmol/l)) exposure variables. Adjusted negative binomial hurdle models were used to investigate the potential associations between serum vitamin D and the oral health outcomes (dental caries and MIH) adjusted for sex, age, body mass index, season of blood draw, and mother's educational level. RESULTS: Of the 101 children in the total sample, 27% had insufficient vitamin D levels (< 50 nmol/l). The descriptive analysis indicated that the children with insufficient vitamin D levels had a higher prevalence (33.3%) and a higher number of teeth affected by dental caries (mean (SD) = 0.7 (1.4)), compared to children with sufficient levels of vitamin D (21.6% and mean (SD) = 0.4 (0.8), respectively). The same holds for MIH, with a higher prevalence (38.5%) and a higher number of teeth affected (mean (SD) = 1.2 (2.3)), compared to children with sufficient levels of vitamin D (30.1% and mean (SD) = 0.8 (1.6), respectively). However, in the adjusted hurdle model analysis, neither the prevalence or number of teeth affected by caries or MIH showed statistically significant associations with having insufficient or lower vitamin D levels. CONCLUSIONS: Vitamin D status was not significantly associated with the prevalence and number of teeth affected by caries and MIH among the participating children. Large prospective studies with multiple serum vitamin D measurements and oral examinations throughout childhood are warranted to elucidate the relationship.

Coupling of the engineered DNA "mutator" to a biosensor as a new paradigm for activation of silent biosynthetic gene clusters in Streptomyces.

DNA replication fidelity in Streptomyces bacteria, prolific producers of many medically important secondary metabolites, is understudied, while in Escherichia coli it is controlled by DnaQ, the ϵ subunit of DNA polymerase III (DNA PolIII). Manipulation of dnaQ paralogues in Streptomyces lividans TK24, did not lead to increased spontaneous mutagenesis in this bacterium suggesting that S. lividans DNA PolIII uses an alternative exonuclease activity for proofreading. In Mycobacterium tuberculosis, such activity is attributed to the DnaE protein representing α subunit of DNA PolIII. Eight DnaE mutants designed based on the literature data were overexpressed in S. lividans, and recombinant strains overexpressing two of these mutants displayed markedly increased frequency of spontaneous mutagenesis (up to 1000-fold higher compared to the control). One of these 'mutators' was combined in S. lividans with a biosensor specific for antibiotic coelimycin, which biosynthetic gene cluster is present but not expressed in this strain. Colonies giving a positive biosensor signal appeared at a frequency of ca 10-5, and all of them were found to produce coelimycin congeners. This result confirmed that our approach can be applied for chemical- and radiation-free mutagenesis in Streptomyces leading to activation of orphan biosynthetic gene clusters and discovery of novel bioactive secondary metabolites.

Body mass index and incidence of lung cancer in the HUNT study: using observational and Mendelian randomization approaches.

BACKGROUND: Traditional observational studies have shown an inverse association between body mass index (BMI) and lung cancer risk. Mendelian randomization (MR) analysis using genetic variants as instruments for BMI may clarify the nature of the association. AIMS: We studied the causal association between BMI and lung cancer incidence using observational and MR approaches. METHODS: We followed up 62,453 cancer-free Norwegian adults from 1995-97 (HUNT2) until 2017. BMI at baseline in HUNT2 was classified as < 25.0, 25.0-29.9 and ≥ 30.0 kg/m2. BMI change over ten years between HUNT1 (1984-86) and HUNT2 was calculated and classified into quartiles. Seventy-five genetic variants were included as instruments for BMI (among which 14 also associated with smoking behavior). Incident lung cancer cases were ascertained from the Cancer Registry of Norway. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Multivariable MR was used to examine the effect of BMI after genetically controlling for smoking. RESULTS: During a median follow-up of 21.1 years, 1009 participants developed lung cancer including 327 with lung adenocarcinoma. The HRs and 95% CIs for incidence of adenocarcinoma were 0.73 (0.58-0.92) for BMI 25.0-29.9 kg/m2 and 0.53 (0.37-0.76) for BMI ≥ 30 kg/m2 compared with BMI < 25.0 kg/m2 in HUNT2 (P for trend < 0.001). However, there was little evidence of a dose-response relationship between the BMI change from HUNT1 to HUNT2 in quartiles and the incidence of adenocarcinoma (P for trend = 0.08). Furthermore, multivariable MR approach suggested a positive association between genetically determined 1 kg/m2 increase in BMI and the incidence of adenocarcinoma (HR 1.25, 95% CI 1.02-1.53). No associations were found with other lung cancer histologic types. CONCLUSIONS: Our study suggests that the inverse association between baseline BMI and lung adenocarcinoma in observational analysis may not be causal. More MR studies are needed to confirm our finding of a positive association between BMI and lung adenocarcinoma.

The validity of self-reported number of teeth and edentulousness among Norwegian older adults, the HUNT Study.

BACKGROUND: Number of teeth is an established indicator of oral health and is commonly self-reported in epidemiological studies due to the costly and labor-intensive nature of clinical examinations. Although previous studies have found self-reported number of teeth to be a reasonably accurate measure, its accuracy among older adults ≥ 70 years is less explored. The aim of this study was to assess the validity of self-reported number of teeth and edentulousness in older adults and to investigate factors that may affect the accuracy of self-reports. METHODS: This study included two different samples of older adults ≥ 70 years drawn from the fourth wave of the Trøndelag Health Study (the HUNT Study), Norway. Sample 1 (n = 586) was used to evaluate the validity of self-reported number of teeth and sample 2 (n = 518) was used to evaluate self-reported edentulousness. Information on number of teeth and background variables (education, smoking, cognitive function, and self-perceived general and oral health) were self-reported in questionnaires, while clinical oral health examinations assessed number of teeth, number of teeth restored or replaced by fixed prosthodontics and edentulousness. Spearman and Pearson correlation coefficients, Bland-Altman plot, chi-square test and kappa statistics were used to assess the agreement between self-reported and clinically recorded number of teeth. RESULTS: The mean difference between self-reported and clinically recorded number of teeth was low (- 0.22 teeth), and more than 70% of the participants reported their number of teeth within an error of two teeth. Correlations between self-reports and clinical examinations were high for the total sample (0.86 (Spearman) and 0.91 (Pearson)). However, a lower correlation was found among participants with dementia (0.74 (Spearman) and 0.85 (Pearson)), participants having ≥ 20 teeth (0.76 (Spearman) and 0.67 (Pearson)), and participants with ≥ 5 teeth restored or replaced by fixed prosthodontics (0.75 (Spearman) and 0.77 (Pearson)). Self-reports of having teeth or being edentulous were correct in 96.3% of the cases (kappa value 0.93, p value < 0.001). CONCLUSIONS: Among older Norwegian adults, self-reported number of teeth agreed closely with clinical tooth counts and nearly all the edentulous participants correctly reported having no teeth.

Adiposity and asthma in adults: a bidirectional Mendelian randomisation analysis of The HUNT Study.

BACKGROUND: We aimed to investigate the potential causal associations of adiposity with asthma overall, asthma by atopic status or by levels of symptom control in a large adult population and stratified by sex. We also investigated the potential for reverse causation between asthma and risk of adiposity. METHODS: We performed a bidirectional one-sample Mendelian randomisation (MR) study using the Norwegian Nord-Trøndelag Health Study population including 56 105 adults. 73 and 47 genetic variants were included as instrumental variables for body mass index (BMI) and waist-to-hip ratio (WHR), respectively. Asthma was defined as ever asthma, doctor-diagnosed asthma and doctor-diagnosed active asthma, and was further classified by atopic status or levels of symptom control. Causal OR was calculated with the Wald method. RESULTS: The ORs per 1 SD (4.1 kg/m2) increase in genetically determined BMI were ranged from 1.36 to 1.49 for the three asthma definitions and similar for women and men. The corresponding ORs for non-atopic asthma (range 1.42-1.72) appeared stronger than those for the atopic asthma (range 1.18-1.26), but they were similar for controlled versus partly controlled doctor-diagnosed active asthma (1.43 vs 1.44). There was no clear association between genetically predicted WHR and asthma risk or between genetically predicted asthma and the adiposity markers. CONCLUSIONS: Our MR study provided evidence of a causal association of BMI with asthma in adults, particularly with non-atopic asthma. There was no clear evidence of a causal link between WHR and asthma or of reverse causation.

Potential causal associations of serum 25-hydroxyvitamin D with lipids: a Mendelian randomization approach of the HUNT study.

Observational studies have shown consistent associations between higher circulating 25-hydroxyvitamin D [25(OH)D] levels and favorable serum lipids. We sought to investigate if such associations were causal. A Mendelian randomization (MR) study was conducted on a population-based cohort comprising 56,435 adults in Norway. A weighted 25(OH)D allele score was generated based on vitamin D-increasing alleles of rs2282679, rs12785878 and rs10741657. Linear regression analyses of serum lipid levels on the allele score were performed to assess the presence of causal associations of serum 25(OH)D with the lipids. To quantify the causal effects, the inverse-variance weighted method was used for calculating MR estimates based on summarized data of individual single-nucleotide polymorphisms. The MR estimate with 95% confidence interval (CI) represents percentage difference in the lipid level per genetically determined 25 nmol/L increase in 25(OH)D. The 25(OH)D allele score demonstrated a clear association with high-density lipoprotein (HDL) cholesterol (p = 0.007) but no association with total or non-HDL cholesterol or triglycerides (p ≥ 0.27). The MR estimate showed 2.52% (95% CI 0.79-4.25%) increase in HDL cholesterol per genetically determined 25 nmol/L increase in 25(OH)D, which was stronger than the corresponding estimate of 1.83% (95% CI 0.85-2.81%) from the observational analysis. The MR estimates for total cholesterol (0.60%, 95% CI - 0.73 to 1.94%), non-HDL cholesterol (0.04%, 95% CI - 1.79 to 1.88%) and triglycerides (- 2.74%, 95% CI - 6.16 to 0.67%) showed no associations. MR analysis of data from a population-based cohort suggested a causal and positive association between serum 25(OH)D and HDL cholesterol.

Serum 25-hydroxyvitamin D levels and risk of lung cancer and histologic types: a Mendelian randomisation analysis of the HUNT study.

We aimed to investigate potential causal associations between serum 25-hydroxyvitamin D (25(OH)D) levels and incidence of lung cancer overall and histologic types.We performed a Mendelian randomisation analysis using a prospective cohort study in Norway, including 54 580 individuals and 676 incident lung cancer cases. A 25(OH)D allele score was generated based on the vitamin D-increasing alleles rs2282679, rs12785878 and rs10741657. Hazard ratios with 95% confidence intervals for incidence of lung cancer and histologic types were estimated in relation to the allele score. The inverse-variance weighted method using summarised data of individual single nucleotide polymorphisms was applied to calculate the Mendelian randomisation estimates.The allele score accounted for 3.4% of the variation in serum 25(OH)D levels. There was no association between the allele score and lung cancer incidence overall, with HR 0.99 (95% CI 0.93-1.06) per allele score. A 25 nmol·L-1 increase in genetically determined 25(OH)D level was not associated with the incidence of lung cancer overall (Mendelian randomisation estimate HR 0.96, 95% CI 0.54-1.69) or any histologic type.Mendelian randomisation analysis did not suggest a causal association between 25(OH)D levels and risk of lung cancer overall or histologic types in this population-based cohort study.

Associations of serum 25-hydroxyvitamin D level with incidence of lung cancer and histologic types in Norwegian adults: a case-cohort analysis of the HUNT study.

Previous prospective studies have shown inconsistent associations between serum 25-hydroxyvitamin D [25(OH)D] level and lung cancer incidence. The aim of the present study was to explore the associations of serum 25(OH)D levels with incidence of lung cancer overall and different histologic types. We performed a population-based prospective case-cohort study including 696 incident lung cancer cases and 5804 individuals in a subcohort who participated in the second survey of the Nord-Trøndelag Health Study in Norway. Cox proportional hazards regression models counting for the case-cohort design were used to estimate hazard ratios (HRs) with 95% confidence interval (CIs) for lung cancer overall or histologic types in relation to serum 25(OH)D levels. Compared with the fourth season-specific quartile of 25(OH)D (median 68.0 nmol/L), lower 25(OH)D levels were not associated with the incidence of overall, small or squamous cell lung cancer. However, the risk of adenocarcinoma was lower in the second and third quartiles (median 39.9 and 51.5 nmol/L) compared with the fourth quartile, with HRs of 0.63 (95% CI 0.41-0.98) and 0.58 (0.38-0.88), respectively. The associations of lower levels of 25(OH)D with a reduced risk of adenocarcinoma were only observed in the overweight/obese subjects [HRs for second and third quartiles: 0.40 (0.22-0.72) and 0.50 (0.27-0.92)] but not in the normal weight subjects [HRs: 0.95 (0.52-1.75) and 0.60 (0.32-1.10)]. Serum 25(OH)D levels were not associated with the risk of lung cancer in general. The observation that lower 25(OH)D levels were associated with a lower risk of adenocarcinoma should be interpreted with caution.

Identification of genes affecting alginate biosynthesis in Pseudomonas fluorescens by screening a transposon insertion library.

BACKGROUND: Polysaccharides often are necessary components of bacterial biofilms and capsules. Production of these biopolymers constitutes a drain on key components in the central carbon metabolism, but so far little is known concerning if and how the cells divide their resources between cell growth and production of exopolysaccharides. Alginate is an industrially important linear polysaccharide synthesized from fructose 6-phosphate by several bacterial species. The aim of this study was to identify genes that are necessary for obtaining a normal level of alginate production in alginate-producing Pseudomonas fluorescens. RESULTS: Polysaccharide biosynthesis is costly, since it utilizes nucleotide sugars and sequesters carbon. Consequently, transcription of the genes necessary for polysaccharide biosynthesis is usually tightly regulated. In this study we used an engineered P. fluorescens SBW25 derivative where all genes encoding the proteins needed for biosynthesis of alginate from fructose 6-phosphate and export of the polymer are expressed from inducible Pm promoters. In this way we would avoid identification of genes merely involved in regulating the expression of the alginate biosynthetic genes. The engineered strain was subjected to random transposon mutagenesis and a library of about 11500 mutants was screened for strains with altered alginate production. Identified inactivated genes were mainly found to encode proteins involved in metabolic pathways related to uptake and utilization of carbon, nitrogen and phosphor sources, biosynthesis of purine and tryptophan and peptidoglycan recycling. CONCLUSIONS: The majority of the identified mutants resulted in diminished alginate biosynthesis while cell yield in most cases were less affected. In some cases, however, a higher final cell yield were measured. The data indicate that when the supplies of fructose 6-phosphate or GTP are diminished, less alginate is produced. This should be taken into account when bacterial strains are designed for industrial polysaccharide production.

Mertk gene expression and photoreceptor outer segment phagocytosis by cultured rat bone marrow mesenchymal stem cells.

BACKGROUND: Bone marrow mesenchymal stem cells (BM-MSCs) are multipotential stem cells that have been used for a broad spectrum of indications. Several investigations have used BM-MSCs to promote photoreceptor survival and suggested that BM-MSCs are a potential source of cell replacement therapy for some forms of retinal degeneration. PURPOSE: To investigate the expression of the MER proto-oncogene, tyrosine kinase (Mertk), involved in the disruption of RPE phagocytosis and the onset of autosomal recessive retinitis pigmentosa in rat BM-MSCs and to compare phagocytosis of the photoreceptor outer segment (POS) by BM-MSCs and RPE cells in vitro. METHODS: MSCs were isolated from the bone marrow of Brown Norway rats. Reverse transcription-PCR (RT-PCR) and western blot analyses were used to examine the expression of Mertk. The phagocytized POS was detected with double fluorescent labeling, transmission electron microscopy, and scanning electron microscopy. RESULTS: Mertk expression did not differ among the first three passages of BM-MSCs. Mertk gene expression was greater in the BM-MSCs than the RPE cells. Mertk protein expression in the BM-MSCs was similar to that in the RPE cells in the primary passage and was greater than that in the RPE cells in the other two passages. BM-MSCs at the first three passages phagocytized the POS more strongly than the RPE cells. The process of BM-MSC phagocytosis was similar to that of the RPE cells. CONCLUSIONS: BM-MSCs may be an effective cell source for treating retinal degeneration in terms of phagocytosis of the POS.

Phenotypic screening of a targeted mutant library reveals Campylobacter jejuni defenses against oxidative stress.

During host colonization, Campylobacter jejuni is exposed to harmful reactive oxygen species (ROS) produced from the host immune system and from the gut microbiota. Consequently, identification and characterization of oxidative stress defenses are important for understanding how C. jejuni survives ROS stress during colonization of the gastrointestinal tract. Previous transcriptomic studies have defined the genes belonging to oxidant stimulons within C. jejuni. We have constructed isogenic deletion mutants of these identified genes to assess their role in oxidative stress survival. Phenotypic screening of 109 isogenic deletion mutants identified 22 genes which were either hypersensitive or hyposensitive to oxidants, demonstrating important roles for these genes in oxidant defense. The significance of these genes in host colonization was also assessed in an in vivo chick model of C. jejuni colonization. Overall, our findings identify an indirect role for motility in resistance to oxidative stress. We found that a nonmotile flagellum mutant, the ΔmotAB mutant, displayed increased sensitivity to oxidants. Restoration of sensitivity to superoxide in the ΔmotAB mutant was achieved by fumarate supplementation or tandem deletion of motAB with ccoQ, suggesting that disruption of the proton gradient across the inner membrane resulted in increased superoxide production in this strain. Furthermore, we have identified genes involved in cation transport and binding, detoxification, and energy metabolism that are also important factors in oxidant defense. This report describes the first isogenic deletion mutant library construction for screening of relevant oxidative stress defense genes within C. jejuni, thus providing a comprehensive analysis of the total set of oxidative stress defenses.

Body mass index and all-cause mortality in HUNT and UK biobank studies: revised non-linear Mendelian randomisation analyses.

OBJECTIVES: To estimate the shape of the causal relationship between body mass index (BMI) and mortality risk in a Mendelian randomisation framework. DESIGN: Mendelian randomisation analyses of two prospective population-based cohorts. SETTING: Individuals of European ancestries living in Norway or the UK. PARTICIPANTS: 56 150 participants from the Trøndelag Health Study (HUNT) in Norway and 366 385 participants from UK Biobank recruited by postal invitation. OUTCOMES: All-cause mortality and cause-specific mortality (cardiovascular, cancer, non-cardiovascular non-cancer). RESULTS: A previously published non-linear Mendelian randomisation analysis of these data using the residual stratification method suggested a J-shaped association between genetically predicted BMI and mortality outcomes with the lowest mortality risk at a BMI of around 25 kg/m2. However, the 'constant genetic effect' assumption required by this method is violated. The reanalysis of these data using the more reliable doubly-ranked stratification method provided some indication of a J-shaped relationship, but with much less certainty as there was less precision in estimates at the lower end of the BMI distribution. Evidence for a harmful effect of reducing BMI at low BMI levels was only present in some analyses, and where present, only below 20 kg/m2. A harmful effect of increasing BMI for all-cause mortality was evident above 25 kg/m2, for cardiovascular mortality above 24 kg/m2, for cancer mortality above 30 kg/m2 and for non-cardiovascular non-cancer mortality above 26 kg/m2. In UK Biobank, the association between genetically predicted BMI and mortality at high BMI levels was stronger in women than in men. CONCLUSION: This research challenges findings from previous conventional observational epidemiology and Mendelian randomisation investigations that the lowest level of mortality risk is at a BMI level of around 25 kg/m2. Our results provide some evidence that reductions in BMI will increase mortality risk for a small proportion of the population, and clear evidence that increases in BMI will increase mortality risk for those with BMI above 25 kg/m2.

Associations of Serum Vitamin D With Dental Caries and Periodontitis: The HUNT Study.

OBJECTIVE: To study the relationships of serum 25-hydroxyvitamin D [25(OH)D] with dental caries and periodontitis in a general Norwegian adult population. METHODS: We analysed a subsample of 1605 participants from the Trøndelag Health Study (HUNT) in Norway that had serum 25(OH)D levels measured in HUNT3 (2006-08) and oral health assessed in the HUNT4 Oral Health Study (2017-19). Negative binomial and Poisson regression models were used to estimate the ratios of means (RMs; for count oral outcomes) and prevalence ratios (PRs; for dichotomous oral outcomes). RESULTS: Serum 25(OH)D was inversely associated with the number of decayed teeth in a dose-response gradient (<30.0 nmol/L: RM 1.41, 95% CI 1.07-1.85; 30.0-49.9 nmol/L: 1.14, 0.98-1.32 and ≥75.0 nmol/L: 0.84, 0.67-1.04, as compared to the 50.0-74.9 nmol/L group, P for trend <.001). Each 25 nmol/L decrease in 25(OH)D level was associated with a 15% (RM 1.15, 95% CI 1.05-1.26) increase in the mean number of decayed teeth. Serum 25(OH)D <30.0 nmol/L was associated with a 35% higher prevalence of severe periodontitis (PR 1.35, 95% CI 1.00-1.83). No association was observed between 25(OH)D and the number of natural teeth. CONCLUSION: The present study suggested that serum 25(OH)D level had an inverse and dose-response association with the number of decayed teeth, and serum 25(OH)D <30 nmol/L was associated with a higher prevalence of severe periodontitis in this Norwegian adult population.

Serum vitamin D, blood pressure and hypertension risk in the HUNT study using observational and Mendelian randomization approaches.

Limited studies have triangulated the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and systolic blood pressure (SBP), diastolic blood pressure (DBP) or hypertension risk utilizing both observational and Mendelian randomization (MR) approaches. We employed data from the Norwegian Trøndelag Health Study (HUNT) to conduct cross-sectional (n = 5854) and prospective (n = 3592) analyses, as well as one-sample MR (n = 86,324). We also used largest publicly available data for two-sample MR. Our cross-sectional analyses showed a 25 nmol/L increase in 25(OH)D was associated with a 1.73 mmHg decrease in SBP (95% CI - 2.46 to - 1.01), a 0.91 mmHg decrease in DBP (95% CI - 1.35 to - 0.47) and 19% lower prevalence of hypertension (OR 0.81, 95% CI 0.74 to 0.90) after adjusting for important confounders. However, these associations disappeared in prospective analyses. One-sample and two-sample MR results further suggested no causal relationship between serum vitamin D levels and blood pressure or hypertension risk in the general population.

Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies (GWASs) on sex hormones and from the Trøndelag Health (HUNT) Study and large consortia on cancers. There was suggestive evidence of genetically predicted 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio (HR) 0.60, 95% CI 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

Estimated cardiorespiratory fitness in relation to overall, breast and prostate cancer incidence: the Norwegian HUNT study.

PURPOSE: To investigate the relationships between the estimated cardiorespiratory fitness (eCRF) and the incidence of overall, breast, and prostate cancer in a large prospective cohort study. METHODS: We included 46,968 cancer-free adults who participated in the second survey of the Trøndelag Health Study in Norway. Sex-specific non-exercise algorithms were used to estimate CRF. eCRF was classified into sex and age-specific tertiles, that is, into low, medium and high levels. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a median of 22.1 years' follow-up, there were 7752 overall, 858 breast and 1376 prostate cancer cases. Medium and high levels of eCRF were associated with a reduced incidence of overall cancer in a dose-response manner in all participants (HR 0.96; 95% CI, 0.90-1.01 and HR 0.85; 95% CI, 0.79-0.91, respectively, and P-value for trend <.001). No association was observed between eCRF and breast cancer incidence in women. Only the high level of eCRF seemed to be associated with a reduced incidence of prostate cancer in men (HR 0.85; 95% CI, 0.72-1.02). CONCLUSIONS: eCRF may be a practical and cost-effective means of investigating the association between the CRF and cancer incidence.

Age at Menarche, age at Natural Menopause, and Risk of Lung and Colorectal Cancers: A Mendelian Randomization Study.

Background: The roles of age at menarche and age at menopause in the etiology of lung and colorectal cancers are unclear. Objective: We aimed to investigate potential causal associations between age at menarche, age at natural menopause, and risk of lung and colorectal cancers using a Mendelian randomization (MR) approach. Methods: From the Trøndelag Health Study in Norway, we defined two cohorts of 35 477 and 17 118 women to study the effects of age at menarche and age at natural menopause, respectively. We ran univariable MR to evaluate the potential causal associations. We performed multivariable MR adjusting for genetic variants of adult body mass index (BMI) to estimate the direct effect of age at menarche. Results: Genetically predicted 1-year increase in age at menarche was associated with a lower risk of lung cancer overall (hazard ratio [HR, 0.64; 95% CI, 0.48-0.86), lung adenocarcinoma (HR, 0.61; 95% CI, 0.38-0.99), and lung non-adenocarcinoma (HR, 0.66; 95% CI, 0.45-0.95). After adjusting for adult BMI using a multivariable MR model, the direct effect estimates reduced to HR 0.72 (95% CI, 0.54-0.95) for lung cancer overall, HR 0.67 (95% CI, 0.43-1.03) for lung adenocarcinoma, and HR 0.77 (95% CI, 0.54-1.09) for lung non-adenocarcinoma. Age at menarche was not associated with colorectal cancer. Moreover, genetically predicted age at natural menopause was not associated with lung and colorectal cancers. Conclusion: Our MR study suggested that later age at menarche was causally associated with a decreased risk of lung cancer overall and its subtypes, and adult BMI might be a mediator.

Prevalence of malnutrition among older adults in a population-based study - the HUNT Study.

BACKGROUND: Malnutrition is common in older adults and is associated with increased morbidity and mortality rates. AIM: The aim of the study is to describe the prevalence of malnutrition based on low BMI, involuntary weight loss, and reduced food intake, in a Norwegian population of community-dwelling older adults and older adults living in nursing homes. METHODS: This population-based study is part of the fourth wave of the Trøndelag Health Study (HUNT4) and includes participants ≥70 years from the HUNT4 70+ cohort. The HUNT4 70+ cohort consist of 9930 (response rate 51.2%) participants. In the current study 8127 older people had complete dataset for inclusion in the analyses. Participants completed a self-report questionnaire and standardised interviews and clinical assessments at field stations, in participants' homes or at nursing homes. Malnutrition was defined using the following criteria: low BMI, involuntary weight loss and severely reduced food intake. The standardised prevalence of malnutrition was estimated using inverse probability weighting (IPW) with weights for sex, age and education of the total population in the catchment area of HUNT. RESULTS: Of the 8127 included participants, 7671 (94.4%) met at field stations, 356 (4.4%) were examined in their home, and 100 (1.2%) in nursing homes. In total, 14.3% of the population were malnourished based on either low BMI, weight loss, or reduced food intake, of which low BMI was the most frequently fulfilled criterion. The prevalence of malnutrition was less common among men than among women (10.1 vs 18.0%, p < 0.001), also after adjustment for age (OR 0.53, 95% confidence interval (CI) 0.46-0.61). The prevalence increased gradually with increasing age and the regression analysis adjusted for sex showed that for each year increase in age the prevalence of malnutrition increased with 4.0% (OR 1.04, 95% CI 1.03-1.05). The prevalence was higher both among older adults examined in their homes (26.4%) and residents in nursing home (23.6%), as compared to community-dwelling older adults who met at field stations (13.5%). CONCLUSION: The prevalence of malnutrition is high in the older population. Special attention on prevention and treatment of malnutrition should be given to older women, the oldest age groups, and care-dependent community-dwelling older adults and nursing home residents.

Increased expression of individual genes in whole blood is associated with late-stage lung cancer at and close to diagnosis.

Lung cancer (LC) mortality rates are still increasing globally. As survival is linked to stage, there is a need to identify markers for earlier LC diagnosis and individualized treatment. The whole blood transcriptome of LC patients represents a source of potential LC biomarkers. We compared expression of > 60,000 genes in whole blood specimens taken from LC cases at diagnosis (n = 128) and controls (n = 62) using genome-wide RNA sequencing, and identified 14 candidate genes associated with LC. High expression of ANXA3, ARG1 and HP was strongly associated with lower survival in late-stage LC cases (hazard ratios (HRs) = 2.81, 2.16 and 2.54, respectively). We validated these markers in two independent population-based studies with pre-diagnostic whole blood specimens taken up to eight years prior to LC diagnosis (n = 163 cases, 184 matched controls). ANXA3 and ARG1 expression was strongly associated with LC in these specimens, especially with late-stage LC within two years of diagnosis (odds ratios (ORs) = 3.47 and 5.00, respectively). Additionally, blood CD4 T cells, NK cells and neutrophils were associated with LC at diagnosis and improved LC discriminative ability beyond candidate genes. Our results indicate that in whole blood, increased expression levels of ANXA3, ARG1 and HP are diagnostic and prognostic markers of late-stage LC.

Cj1386 is an ankyrin-containing protein involved in heme trafficking to catalase in Campylobacter jejuni.

Campylobacter jejuni, a microaerophilic bacterium, is the most frequent cause of human bacterial gastroenteritis. C. jejuni is exposed to harmful reactive oxygen species (ROS) produced during its own normal metabolic processes and during infection from the host immune system and from host intestinal microbiota. These ROS will damage DNA and proteins and cause peroxidation of lipids. Consequently, identifying ROS defense mechanisms is important for understanding how Campylobacter survives this environmental stress during infection. Construction of a ΔCj1386 isogenic deletion mutant and phenotypic assays led to its discovery as a novel oxidative stress defense gene. The ΔCj1386 mutant has an increased sensitivity toward hydrogen peroxide. The Cj1386 gene is located directly downstream from katA (catalase) in the C. jejuni genome. A ΔkatAΔ Cj1386 double deletion mutant was constructed and exhibited a sensitivity to hydrogen peroxide similar to that seen in the ΔCj1386 and ΔkatA single deletion mutants. This observation suggests that Cj1386 may be involved in the same detoxification pathway as catalase. Despite identical KatA abundances, catalase activity assays showed that the ΔCj1386 mutant had a reduced catalase activity relative to that of wild-type C. jejuni. Heme quantification of KatA protein from the ΔCj1386 mutant revealed a significant decrease in heme concentration. This indicates an important role for Cj1386 in heme trafficking to KatA within C. jejuni. Interestingly, the ΔCj1386 mutant had a reduced ability to colonize the ceca of chicks and was outcompeted by the wild-type strain for colonization of the gastrointestinal tract of neonate piglets. These results indicate an important role for Cj1386 in Campylobacter colonization and pathogenesis.