The effectiveness of pollen allergen immunotherapy on allergic rhinitis over 18 years: A national cohort study in Denmark.

BACKGROUND: Because long-term effectiveness of pollen allergen immune therapy (AIT) for allergic rhinitis (AR) is not well-described, we studied effectiveness over 18 years in Denmark. METHODS: A register-based cohort study using data on filled prescriptions, 1995-2016, Denmark. In a cohort of 1.1 million intranasal corticosteroid inhaler users (proxy for AR), we matched users treated with grass, birch or mugwort AIT 1:2 with non-treated users on baseline year and 24 characteristics in the 3 years prior to baseline. The primary outcome was the odds ratio (OR) of using anti-allergic nasal inhaler during the pollen season in the treated versus non-treated group by years since baseline. RESULTS: Among 7760 AR patients treated with pollen AIT, the OR of using nasal inhaler 0-5 years after baseline was reduced when compared with 15,520 non-treated AR individuals (0-2 years, OR 0.84 (0.81-0.88); 3-5 years, OR 0.88 (0.84-0.92)), but was close to unity or higher thereafter (6-9 years, OR 1.03 (0.97-1.08); 10-18 years, OR 1.18 (1.11-1.26)). In post hoc analyses, results were more consistent for those who already had 3 of 3 baseline years of use, and in patients using nasal inhaler in the latest pollen season (0-2 years, OR 0.76 (0.72-0.79); 3-5 years OR 0.86 (0.81-0.93); 6-9 years, OR 0.94 (0.87-1.02); 10-18 years, OR 0.94 (0.86-1.04)) as opposed to no such use. CONCLUSIONS: Patients treated with pollen AIT in routine care to a higher degree stopped using anti-allergic nasal inhaler 0-5 years after starting the standard 3 years of therapy, and not beyond 5 years. Post hoc analyses suggested effectiveness was more consistent among patients with persistent AR.

Association Between Maternal Folic Acid Supplementation and Congenital Heart Defects in Offspring in Birth Cohorts From Denmark and Norway.

Background Evidence linking individual-level maternal folic acid supplementation to offspring risk of congenital heart defects is lacking. We investigated whether folic acid supplementation in early pregnancy reduces offspring risk of heart defects in 2 large birth cohort studies. Methods and Results Women recruited in early pregnancy within the DNBC (Danish National Birth Cohort), 1996-2003, and MoBa (Norwegian Mother and Child Cohort Study), 2000-2009, were followed until delivery. Information on periconceptional intake of folic acid and other supplements was linked with information on heart defects from national registers. Among 197 123 births, we identified 2247 individuals with heart defects (114/10 000). Periconceptional (4 weeks before through 8 weeks after conception) use of folic acid plus other supplements (54.8%), folic acid only (12.2%), and non-folic acid supplements (5.0%) were compared with no supplement use (28.0%); the adjusted relative risks of heart defects were 0.99 (95% CI, 0.80-1.22), 1.08 (95% CI , 0.93-1.25), and 1.07 (95% CI , 0.97-1.19), respectively. For initiation of folic acid in the preconception period weeks -4 to -1 (33.7%) and the postconception periods 0 to 4 weeks (15.5%), 5 to 8 weeks (17.8%), and 9 to 12 weeks (4.6%), compared with no or late folic acid intake (29.1%), relative risks of heart defect were 1.11 (95% CI , 1.00-1.25), 1.09 (95% CI , 0.95-1.25), 0.98 (95% CI , 0.86-1.12), and 0.97 (95% CI , 0.78-1.20), respectively. Relative risks of severe defects, conotruncal defects, and septal defects showed similar results. Conclusions Folic acid was not associated with offspring risk of heart defects, including severe defects, conotruncal defects, or septal defects.

Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation.

BACKGROUND: The comparative effectiveness and safety of individual direct oral anticoagulants (DOACs) in clinical practice is largely unknown. The study objectives were to compare effectiveness and safety of DOACs in patients with non-valvular atrial fibrillation (NVAF). METHODS: Based on nationwide registers we established a population-based historical cohort study of 12,638 new users of standard dose DOACs (apixaban 5 mg twice daily, dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily) with NVAF in Denmark, July 2013 to March 2016. Patients were matched on propensity scores in a 1:1 ratio comparing apixaban vs. dabigatran (for a total of 6470 patients), apixaban vs. rivaroxaban (7352 patients), and rivaroxaban vs. dabigatran (5440 patients). Hazard ratios (HRs) for stroke or systemic embolism (effectiveness outcome) and major bleeding (safety outcome) were estimated. RESULTS: In propensity-matched comparisons of the risk of stroke or systemic embolism, the HRs were 1.27 (95% confidence interval [CI], 0.82-1.96) for apixaban vs. dabigatran, 1.25 (95% CI, 0.87-1.79) for apixaban vs. rivaroxaban, and 1.17 (95% CI, 0.69-1.96) for rivaroxaban vs. dabigatran. For the risk of major bleeding, the HRs were 0.94 (95% CI, 0.62-1.41) for apixaban vs. dabigatran, 0.88 (95% CI, 0.64-1.22) for apixaban vs. rivaroxaban, and 1.35 (95% CI, 0.91-2.00) for rivaroxaban vs. dabigatran. CONCLUSIONS: Among patients with NVAF in routine clinical practice, there were no statistically significant differences in risk of stroke or systemic embolism or major bleeding in propensity-matched comparisons between apixaban, dabigatran, and rivaroxaban used in standard doses. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out.

Supplemental folic acid in pregnancy and childhood cancer risk.

BACKGROUND: We investigated the association between supplemental folic acid in pregnancy and childhood cancer in a nation-wide study of 687 406 live births in Norway, 1999-2010, and 799 children diagnosed later with cancer. METHODS: Adjusted hazard ratios (HRs) compared cancer risk in children by approximated periconceptional folic acid levels (folic acid tablets and multivitamins (0.6 mg), only folic acid (0.4 mg), only multivitamins (0.2 mg)) and cancer risk in unexposed. RESULTS: Any folic acid levels were not associated with leukemia (e.g., high-level folic acid HR 1.25; 95% CI 0.89-1.76, PTrend 0.20), lymphoma (HR 0.96; 95% CI 0.42-2.21, PTrend 0.51), central nervous system tumours (HR 0.68; 95% CI 0.42-1.10, PTrend 0.32), neuroblastoma (HR 1.05; 95% CI 0.53-2.06, PTrend 0.85), Wilms' tumour (HR 1.16; 95% CI 0.52-2.58, PTrend 0.76), or soft-tissue tumours (HR 0.77; 95% CI 0.34-1.75, PTrend 0.90). CONCLUSIONS: Folic acid supplementation was not associated with risk of major childhood cancers.

Supplemental folic acid in pregnancy and maternal cancer risk.

BACKGROUND: There is evidence that increased intake of folate protects against the development of several types of cancer. Some studies have, however, raised concern about the safety of folate in relation to cancer risk. Here we examined the risk of maternal cancer after intake of supplemental folic acid in pregnancy. METHODS: This is a population-based cohort study comprising 429,004 women with data from the Medical Birth Registry of Norway, the Cancer Registry of Norway, and other national registries from 1999 to 2010. Altogether 3781 cancer cases were identified during follow-up (average 7 years). Cox proportional hazards regression models were used to estimate hazard ratios of maternal cancer according to folic acid use prior to and during one or two or more pregnancies as compared to no supplement use. RESULTS: Folic acid supplementation use had no overall effect on cancer risk in women using folic acid supplementation in one (HR 1.08; 95% CI 1.00-1.18) or two or more pregnancies (HR 1.06; 95% CI 0.91-1.22) (ptrend=0.12). Analyses of 13 cancer types revealed no associations between folic acid and cancer. CONCLUSION: Folic acid supplementation before and during pregnancy had no overall effect on maternal cancer risk. IMPACT: Folic acid substitution before and/or during pregnancy does not increase the short-term overall maternal cancer risk.

Decrease in vitamin D status in the Greenlandic adult population from 1987-2010.

BACKGROUND: Low vitamin D status may be pronounced in Arctic populations due to limited sun exposure and decreasing intake of traditional food. OBJECTIVE: To investigate serum 25(OH)D3 as a measure of vitamin D status among adult Inuit in Greenland, predictors of low serum 25(OH)D3 concentrations and the trend from 1987 to 2005-2010. DESIGN: A total of 2877 randomly selected Inuit (≥ 18 years) from the Inuit Health in Transition study were included. A sub-sample (n = 330) donated a blood sample in 1987 which allowed assessment of time trends in vitamin D status. RESULTS: The geometric mean serum 25(OH)D3 (25[OH]D2 concentrations were negligible and not reported) in 2005-2010 was lowest among the 18-29 year old individuals (30.7 nmol/L; 95% CI: 29.7; 31.7) and increased with age. In all age-groups it decreased from 1987 to 2005-2010 (32%-58%). Low 25(OH)D3 concentrations (<50 nmol/L) were present in 77% of the 18-29 year old and decreased with age. A characteristic seasonal variation in 25(OH)D3 concentrations was observed (range 33.2-57.1 nmol/L, p<0.001), with the highest concentrations in August to October. Age (2.0% per year increase; CI: 1.7, 2.2), female gender (7.1%; CI: 2.0; 12.5), alcohol intake (0.2% per increase in drinks/week; 0.0; 0.4), and traditional diet (10.0% per 100 g/d increase; CI: 7.9; 12.1) were associated with increased serum 25(OH)D3, whereas smoking (-11.6%; CI: -16.2; -6.9), BMI (-0.6%; CI: -1.1; -0.2) and latitude (-0.7% per degree increase; CI: -1.3; -0.2) were associated with decreased concentrations. CONCLUSION: We identified a remarkable decrease in vitamin D status from 1987 to 2005-2010 and a presently low vitamin D status among Inuit in Greenland. A change away from a traditional diet may well explain the observed decline. The study argues for the need of increased dietary intake of vitamin D and supplementation might be considered.

Digoxin use and the risk of cancers of the corpus uteri, ovary and cervix.

Digoxin is a phyto-estrogen capable of inducing hormonal effects. Use has been associated with increased risk of breast cancer, an estrogen-sensitive malignancy. The incidence of corpus uteri (uterus) cancer is also strongly increased with exposure to estrogens. Therefore, we evaluated whether digoxin use might also increase its incidence. In all women in Denmark, we identified digoxin users from 1995 through 2008 using a nationwide pharmacy registry system. Cancer occurrence was obtained from Danish Cancer Registry. Relative risk was determined using incidence risk ratios (RR) and 95% confidence intervals (CIs) relative to non-users after adjustment for age- and calendar-time. For ovarian and cervical cancers, RRs in users and non-users were similarly evaluated, these cancers representing gynecological cancers with weak or no associations to estrogen exposure. Of 2.1 million women, 104,648 (4.9%) had digoxin exposure and 137,493 6.5% had exposure to angina drugs but not digoxin during the study period. For uterus cancer, the RR was increased in current digoxin users (1.48, 95% CI: 1.32-1.65; N = 350). Incidence was marginally increased in former users. For ovary and cervix cancers, RRs in current digoxin users were 1.06 (95% CI: 0.92-1.22; N = 207) and 1.00 (95% CI: 0.79-1.25; N = 81), respectively. We examined risks in women using angina drugs but not digoxin to determine whether being under cardiac care affected risk. Among women using angina drugs only, RRs for uterus, ovary or cervix cancers were not statistically significant. We conclude that women currently using digoxin, a phyto-estrogen, have an increased risk of developing uterus cancers.

Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption.

Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), The Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4 · 10(-14)) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3 · 10(-11)). An effect of ∼0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and non-smokers.

Both high and low serum vitamin D concentrations are associated with tuberculosis: a case-control study in Greenland.

Vitamin D deficiency has been associated with increased risk of tuberculosis (TB). Changes from a traditional to a Westernised diet among Greenlanders have resulted in reduced serum vitamin D, leading to considerations of whether preventive vitamin D supplementation should be introduced. The association between vitamin D status and TB was examined to assess the feasibility of vitamin D supplementation in Greenland. This was examined in a case-control study involving seventy-two matched pairs of TB patients (cases) and controls aged 8-74 years. Cases were diagnosed with TB during 2004-6 based on clinical findings in combination with either (1) positive Mycobacterium tuberculosis culture, (2) characteristic X-ray abnormalities together with a positive tuberculin skin test or a positive interferon-γ release assay or (3) characteristic histology. Controls were individually matched on age ( ± 5 years), sex and district. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured and OR of TB were the outcome. Compared with individuals with 25(OH)D concentrations between 75 and 140 nmol/l, individuals with concentrations < 75 nmol/l (OR 6.5; 95% CI 1.8, 23.5) or > 140 nmol/l (OR 6.5; 95% CI 1.9, 22.2) had higher risks of active TB (P = 0.003; adjustment for alcohol and ethnicity). Supplementing individuals with low vitamin D to normalise serum 25(OH)D concentrations was estimated to result in a 29% reduction in the number of TB cases. The study indicated that vitamin D supplementation may be beneficial to individuals with insufficient vitamin D concentrations but may increase the risk of TB among individuals with normal or high concentrations.

In-utero exposure to smoking, alcohol, coffee, and tea and risk of strabismus.

In a prospective, population-based cohort study, the authors investigated the effect of in-utero exposure to maternal smoking and consumption of alcohol, coffee, and tea on the risk of strabismus. They reviewed medical records for children in the Danish National Birth Cohort identified through national registers as possibly having strabismus. Relative risk estimates were adjusted for year of birth, social class, maternal smoking, maternal age at birth, and maternal coffee and tea consumption. The authors identified 1,321 cases of strabismus in a cohort of 96,842 Danish children born between 1996 and 2003. Maternal smoking was associated with a significantly elevated risk of strabismus in the child, increasing with number of cigarettes smoked per day (<5 cigarettes/day: relative risk (RR) = 0.95, 95% confidence interval (CI): 0.80, 1.14; 5-<10 cigarettes/day: RR = 1.38, 95% CI: 1.12, 1.70; > or =10 cigarettes/day: RR = 1.90, 95% CI: 1.57, 2.30). Nicotine replacement therapy was not associated with strabismus risk (RR = 1.22, 95% CI: 0.92, 1.61). Light maternal alcohol consumption was inversely associated with strabismus risk, whereas maternal coffee and tea drinking were not associated with strabismus risk. In conclusion, smoking during pregnancy is associated with an increased risk of strabismus in the offspring. Conversely, light alcohol consumption is associated with decreased risk.

Recurrence of discordant congenital heart defects in families.

BACKGROUND: Variation within a single gene might produce different congenital heart defects (CHDs) within a family, which could explain the previously reported familial aggregation of discordant CHDs. We investigated whether certain groups of discordant CHDs are more common in families than others. METHODS AND RESULTS: Using Danish national population and health registers, we identified CHDs among all singletons born in Denmark during 1977-2005 and their first-degree relatives. In a cohort of 1 711 641 persons, 16 777 had CHDs, which we classified into 14 phenotypes. We estimated relative risks of discordant CHDs by history of specific CHDs in first-degree relatives. The relative risk of any dissimilar CHD given the specified CHD in first-degree relatives was as follows: heterotaxia, 2.00 (95% CI, 0.96 to 4.17); conotruncal defects, 2.78 (95% CI, 2.12 to 3.66); atrioventricular septal defects, 2.25 (95% CI, 1.39 to 3.66); anomalous pulmonary venous return, 1.76 (95% CI, 0.66 to 4.64); left- and right-ventricular outflow tract obstruction, 2.55 (95% CI, 1.87 to 3.48) and 3.09 (95% CI, 2.03 to 4.71), respectively; isolated atrial septal defects, 2.76 (95% CI, 2.11 to 3.61); isolated ventricular septal defects, 2.27 (95% CI, 1.75 to 2.94); persistent ductus arteriosus, 1.92 (95% CI, 1.32 to 2.79); other specified CHDs, 3.29 (95% CI, 2.51 to 4.32); and unspecified CHDs, 2.30 (95% CI, 1.76 to 3.00). Relative risks for all pairwise combinations of discordant CHD phenotypes gave no indications that certain constellations of CHDs cluster more in families than others. CONCLUSIONS: We documented strong familial aggregation of discordant CHD phenotypes. However, we observed no excess clustering of specific CHD phenotypes among the first-degree relatives.

Trichuris suis ova therapy for allergic rhinitis: a randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Parasitic helminth infections can protect against allergic airway inflammation in experimental models and have been associated with a reduced risk of atopy and a reduced course of asthma in some observational studies. Although no clinical evidence exists to support the use of helminth therapy for allergic disease, the helminth Trichuris suis has demonstrated efficacy in treatment of inflammatory bowel disease. OBJECTIVE: To determine efficacy of helminth therapy for allergic rhinitis. METHODS: We conducted a double-blind, placebo-controlled, parallel group trial in which 100 subjects age 18 to 65 years with grass pollen-induced allergic rhinitis were randomly assigned to ingest a total of 8 doses with 2500 live T suis ova or placebo with an interval of 21 days. The primary outcome was a change in mean daily total symptom score for runny, itchy, sneezing nose (maximum change, 9.0) or in percentage of well days during the grass pollen season. RESULTS: Treatment with T suis ova (N = 49) compared with placebo (N = 47) caused transient diarrhea peaking at day 41 in 33% of participants (placebo, 2%), and increased eosinophil counts (P < .001) and T suis-specific IgE (P < .05), IgG (P < .001), IgG(4) (P < .003), and IgA (P < .001), whereas there was no significant change in symptom scores (0.0; 95% CI, -0.5 to 0.4; P = .87), well days (3%; 95% CI, -9% to 14%; P = .63), total histamine (P = .44), grass-specific IgE (P = .76), or diameter of wheal reaction on skin prick testing with grass (P = .85) or 9 other allergens. CONCLUSION: Repeated treatment with the helminth T suis induced a substantial clinical and immunologic response as evidence of infection, but had no therapeutic effect on allergic rhinitis.