Polycystic ovary syndrome and offspring risk of congenital heart defects: a nationwide cohort study.

STUDY QUESTION: Is maternal polycystic ovary syndrome (PCOS) associated with increased offspring risk of congenital heart defects? SUMMARY ANSWER: This study does not support a strong association between PCOS and an increased risk of congenital heart defects. WHAT IS KNOWN ALREADY: In addition to affecting reproductive health, PCOS may involve insulin resistance. Maternal pregestational diabetes is associated with an increased risk of congenital heart defects and therefore PCOS may increase the risk of congenital heart defects in the offspring. STUDY DESIGN, SIZE, DURATION: In this nationwide cohort study, we used data from Danish health registers collected from 1995 to 2018. The study included 1 302 648 offspring and their mothers. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were live singleton offspring born during the study period. Information on maternal PCOS and offspring congenital heart defects was obtained from the National Patient Register. Logistic regression analysis was used to compute prevalence (odds) ratio (PR) of the association between PCOS and offspring congenital heart defects. MAIN RESULTS AND THE ROLE OF CHANCE: Among 1 302 648 live-born singletons, 11 804 had a mother with PCOS. Of these, 143 offspring had a congenital heart defect (prevalence 121 per 10 000) as compared with 12 832 among mothers without PCOS (prevalence 99 per 10 000). The adjusted PR was 1.22, 95% CI 1.03-1.44 comparing prevalence of congenital heart defects in offspring of women with PCOS with offspring of women without. After adjusting for the potentially mediating effect of pregestational diabetes, the PR was 1.16, 95% CI 0.98-1.37. LIMITATIONS, REASONS FOR CAUTION: PCOS may be underdetected in the National Patient Register. However, we expect that the mothers that we identified with PCOS truly had PCOS, thus, the estimated associations are not likely to be affected by this misclassification. The study does not provide evidence to rule out a moderate or weak association. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide reassurance to clinicians counselling pregnant women with PCOS that the disease does not pose a markedly increased risk of offspring congenital heart defects. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Novo Nordisk Foundation. M.L. reports personal fees from Dansk Lægemiddel Information A/S outside the submitted work. The remaining authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Assessing the Microbiota of Black Soldier Fly Larvae (Hermetia illucens) Reared on Organic Waste Streams on Four Different Locations at Laboratory and Large Scale.

This study aimed to gain insight into the microbial quality, safety and bacterial community composition of black soldier fly larvae (Hermetia illucens) reared at different facilities on a variety of organic waste streams. For seven rearing cycles, both on laboratory-scale and in large-scale facilities at several locations, the microbiota of the larvae was studied. Also samples of the substrate used and the residue (= leftover substrate after rearing, existing of non-consumed substrate, exuviae and faeces) were investigated. Depending on the sample, it was subjected to plate counting, Illumina Miseq sequencing and/or detection of specific food pathogens. The results revealed that the substrates applied at the various locations differed substantially in microbial numbers as well as in the bacterial community composition. Furthermore, little similarity was observed between the microbiota of the substrate and that of the larvae reared on that substrate. Despite substantial differences between the microbiota of larvae reared at several locations, 48 species-level operational taxonomic units (OTUs) were shared by all larvae, among which most belonged to the phyla Firmicutes and Proteobacteria. Although the substrate is assumed to be an important source of bacteria, our results suggest that a variety of supposedly interacting factors-both abiotic and biotic-are likely to affect the microbiota in the larvae. In some larvae and/or residue samples, potential foodborne pathogens such as Salmonella and Bacillus cereus were detected, emphasising that decontamination technologies are required when the larvae are used in feed, just as for other feed ingredients, or eventually in food.

Plasma Concentrations of Long Chain N-3 Fatty Acids in Early and Mid-Pregnancy and Risk of Early Preterm Birth.

BACKGROUND: Fish oil supplementation has been shown to delay spontaneous delivery, but the levels and clinical significance remain uncertain. We examined the association between plasma fatty acids quantified in pregnancy and subsequent risk of early preterm birth. METHODS: In a case-control design nested in the Danish National Birth Cohort, we identified 376 early preterm cases (<34 gestational weeks, excluding preeclampsia cases) and 348 random controls. Plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA% of total fatty acids), were measured twice in pregnancy, at gestation weeks 9 and 25 (medians). Odds ratios and 95% confidence intervals (CI's) for associations between EPA+DHA and early preterm risk were estimated by logistic regression, adjusted for the woman's age, height, pre-pregnancy BMI, parity, smoking, and socioeconomic factors. Hypotheses and analytical plan were defined and archived a priori. FINDINGS: Analysis using restricted cubic splines of the mean of 1st and 2nd sample measurements showed a strong and significant non-linear association (p < 0.0001) in which the risk of early preterm birth steeply increased when EPA+DHA concentrations were lower than 2% and flattened out at higher levels. Women in the lowest quintile (EPA+DHA < 1.6%) had 10.27 times (95% confidence interval 6.80-15.79, p < 0.0001) increased risk, and women in the second lowest quintile had 2.86 (95% CI 1.79-4.59, p < 0.0001) times increased risk, when compared to women in the three aggregated highest quintiles (EPA+DHA ≥ 1.8%). INTERPRETATION: Low plasma concentration of EPA and DHA during pregnancy is a strong risk factor for subsequent early preterm birth in Danish women.

Impact of particulate deproteinized bovine bone mineral and porous titanium granules on early stability and osseointegration of dental implants in narrow marginal circumferential bone defects.

The use of two particulate bone graft substitute materials in experimental narrow marginal peri-implant bone defects was investigated with respect to early bone healing and implant stability. Porous titanium granules, oxidized white porous titanium granules (WPTG), and demineralized bovine bone mineral (DBBM) were characterized in vitro, after which the two latter materials were tested in experimental peri-implant bone defects in six minipigs, with empty defects as control. After mandibular premolar extraction, the top 5mm of the alveoli were widened to 6mm in diameter, followed by the placement of six implants, three on each side, in each pig. Six weeks of healing was allowed. The WPTG showed better mechanical properties. No significant differences in resonance frequency analysis were found directly after compacting or healing, and similar quantities of defect bone formation were observed on micro-computed tomography for all groups. Histomorphometric analysis demonstrated a more coronal bone-to-implant contact in the DBBM group, which also displayed more defect bone fill as compared to the WPTG group. The better mechanical properties observed for WPTG appear of negligible relevance for the early stability and osseointegration of implants.

A novel non-surgical method for mild peri-implantitis- a multicenter consecutive case series.

AIM: The aim of the present study was to evaluate the effect on peri-implant mucosal inflammation from the use of a novel instrument made of chitosan in the non-surgical treatment of mild peri-implantitis across several clinical centers. MATERIALS AND METHODS: In this 6-month multicenter prospective consecutive case series performed in six different periodontal specialist clinics, 63 implants in 63 patients were finally included. The subjects had mild peri-implantitis defined as radiographic bone loss of 1-2 mm, pocket probing depth (PPD) ≥4 mm and a positive bleeding on probing (mBoP) score. The patients were clinically examined at baseline and after 2, 4, 12 and 24 weeks, and radiographs were taken at baseline and at 3 and 6 months. Treatment of the implants with the chitosan brush seated in an oscillating dental drill piece was performed at baseline and at 3 months. Reductions in the clinical parameters (PPD and mBoP) were compared between baseline and the later examination time points. RESULTS: Significant reductions in both PPD and mBoP were observed at all time points compared with the baseline clinical measurements (p < 0.001). The mean PPD and mBoP at baseline were 5.15 mm (4.97; 5.32) and 1.86 (1.78; 1.93), respectively, whereas the mean PPD and mBoP at 6 months were 4.0 mm (3.91; 4.19) and 0.64 (0.54; 0.75), respectively. Stable reductions in PPD and mBoP were evident up to 6 months after the initial treatment and 3 months after the second treatment. All 63 implants were reported to have stable radiographic levels of osseous support. CONCLUSIONS: This case series demonstrated that an oscillating chitosan brush is safe to use and seems to have merits in the non-surgical treatment of dental implants with mild peri-implantitis. To measure the effectiveness of the method, a multicenter randomized clinical trial needs to be undertaken.

The role of filaggrin mutations during pregnancy and postpartum: atopic dermatitis and genital skin diseases.

Mutations in the epidermal filaggrin gene (FLG) are associated with skin barrier dysfunction (dry skin, less acidic skin, and fissured skin), and atopic dermatitis (AD) with a severe and persistent course. Because pregnancy and delivery further impairs normal skin barrier functions (immune suppression, mechanical stress), we studied the possible role of FLG mutations on the risk of AD flares, genital infections, and postpartum problems related to perineal trauma. FLG-genotyping was performed in a population-based sample of 1837 women interviewed in the 12th and 30th weeks of pregnancy and 6 months postpartum as part of the Danish National Birth Cohort study 1996-2002. We found that FLG mutations also influence pregnancy-related skin disease; thus, women with FLG mutations had an increased risk of AD flares during pregnancy (OR 10.5, 95% CI 3.6-30.5) and of enduring postpartum physical problems linked to perineal trauma during delivery (OR 11.1, 95% CI 1.1-107.7).

Non-specific effects of BCG vaccination on morbidity among children in Greenland: a population-based cohort study.

Background: The potential non-specific effects of BCG (Bacillus Calmette-Guérin) vaccination, with reported reduction of infectious disease morbidity among vaccinated children, in addition to the protective effect against tuberculosis (TB), are highly debated. In Greenland, BCG vaccination was introduced in 1955, but temporarily discontinued from 1991 to 1996 due to nationwide policy changes. Using the transient vaccination stop, we aimed to investigate possible non-specific effects of BCG vaccination by measuring nation-wide hospitalization rates due to infectious diseases other than TB among vaccinated and unvaccinated children. Methods: A retrospective cohort study including all children born in Greenland aged 3 months to 3 years from 1989 to 2004. A personal identification number assigned at birth allowed for follow-up through national registers. Information on hospitalization due to infectious diseases was obtained from the Greenlandic inpatient register using ICD-8 and ICD-10 codes. Participants with notified TB were censored. Incidence rate ratios (IRR) were estimated using Poisson regression. Results: Overall, 19 363 children, hereof 66% BCG-vaccinated, were followed for 44 065 person-years and had 2069 hospitalizations due to infectious diseases. IRRs of hospitalization in BCG-vaccinated as compared with BCG-unvaccinated children were 1.07 [95% confidence interval (CI) 0.96-1.20] for infectious diseases overall, and specifically 1.10 (95% CI 0.98-1.24) for respiratory tract infections. Among BCG-vaccinated children aged 3 to 11 months, the IRR of hospitalization due to infectious diseases was 1.00 (95% CI 0.84-1.19) as compared with BCG-unvaccinated children. Conclusion: Our results do not support the hypothesis that neonatal BCG vaccination reduces morbidity in children caused by infectious diseases other than TB.

Mitochondrial dysfunction and risk of cancer.

BACKGROUND: Mitochondrial mutations are commonly reported in tumours, but it is unclear whether impaired mitochondrial function per se is a cause or consequence of cancer. To elucidate this, we examined the risk of cancer in a nationwide cohort of patients with mitochondrial dysfunction. METHODS: We used nationwide results on genetic testing for mitochondrial disease and the Danish Civil Registration System, to construct a cohort of 311 patients with mitochondrial dysfunction. A total of 177 cohort members were identified from genetic testing and 134 genetically untested cohort members were matrilineal relatives to a cohort member with a genetically confirmed maternally inherited mDNA mutation. Information on cancer was obtained by linkage to the Danish Cancer Register. Standardised incidence ratios (SIRs) were used to assess the relative risk of cancer. RESULTS: During 7334 person-years of follow-up, 19 subjects developed a primary cancer. The corresponding SIR for any primary cancer was 1.06 (95% confidence interval 0.68-1.63). Subgroup analyses according to mutational subtype yielded similar results, for example, a SIR of 0.94 (95% CI 0.53 to 1.67) for the m.3243A>G maternally inherited mDNA mutation, cases=13. CONCLUSIONS: Patients with mitochondrial dysfunction do not appear to be at increased risk of cancer compared with the general population.

The effectiveness of BCG vaccination in preventing Mycobacterium tuberculosis infection and disease in Greenland.

BACKGROUND: The BCG vaccine's ability to prevent Mycobacterium tuberculosis infection (MTI) remains highly debated. In Greenland, BCG vaccination was introduced in 1955, but was temporarily discontinued (1991-1996) due to nationwide policy changes. The study aimed to use the transient stop in BCG vaccination to evaluate the effect of vaccination on MTI prevalence and TB incidence. METHODS: MTI study: A cross-sectional study (2012), comprising East Greenlanders born during 1982-2006, evaluated the effect of BCG vaccination on MTI prevalence; a positive interferon γ release assay defined an MTI case. Associations were estimated using logistic regression. TB study: a cohort study covering the same birth cohorts with follow-up until 2012 evaluated the vaccine's effect on TB incidence. A personal identifier allowed for follow-up in the TB notification system. Associations were estimated using Cox regression. RESULTS: MTI study: Included 953 participants; 81% were BCG-vaccinated; 29% had MTI, 23% among vaccinated and 57% among non-vaccinated. BCG vaccination reduced the odds of MTI, OR 0.52 (95% CI 0.32 to 0.85), p=0.01. Vaccine effectiveness against MTI was 20%. TB study: Included 1697 participants followed for 21,148 person-years. 6% were notified with TB, 4% among vaccinated and 11% among non-vaccinated. BCG vaccination reduced the risk of TB, HR 0.50 (95% CI 0.26 to 0.95), p=0.03, yielding a vaccine effectiveness of 50%. CONCLUSIONS: BCG vaccination was effective in reducing both MTI and TB disease among children and young adults in a TB high-endemic setting in Greenland.

Risk of cancer in relatives of patients with myotonic dystrophy: a population-based cohort study.

BACKGROUND AND PURPOSE: Myotonic dystrophies (DM) are autosomal dominantly inherited neuromuscular disorders caused by unstable nucleotide repeat expansions. DM and cancer have been associated, but the pathogenesis behind the association remains unclear. It could relate to derived effects of the DM genotype in which case non-DM relatives of DM patients would not be expected to be at increased risk of cancer. To elucidate this, a population-based cohort study investigating risk of cancer in relatives of DM patients was conducted. METHODS: DM was identified using the National Danish Patient Registry and results of genetic testing. Information on cancer was obtained from the Danish Cancer Registry. A population-based cohort of 5 757 565 individuals with at least one relative was established using the Danish Family Relations Database based on kinship links in the Danish Civil Registration System. Familial aggregation of cancer was evaluated by (incidence) rate ratios (RRs) comparing the rate of cancer amongst relatives of patients with DM from 1977 to 2010 (exposed) with the rate of cancer amongst persons with a relative of the same type but without DM (non-exposed). RESULTS: In first-degree relatives of individuals with DM the adjusted RR of cancer was 0.89 (95% confidence interval 0.71-1.12) overall, and in stratified analyses 0.68 (0.37-1.12) before age 50 and 0.96 (0.74-1.23) at age 50 or older. CONCLUSIONS: The present study does not support an increased risk of cancer in non-DM relatives of DM patients suggesting that cancer and DM are associated through derived effects of the DM genotype.

Clinical predictors to identify paroxysmal atrial fibrillation after ischaemic stroke.

BACKGROUND AND PURPOSE: Detection of paroxysmal atrial fibrillation (pAF) after an ischaemic cerebrovascular event is of imminent interest, because oral anticoagulation as a highly effective secondary preventive treatment is available. Whereas permanent atrial fibrillation (AF) can be detected during routine electrocardiogram (ECG), longer detection duration will detect more pAF but might be resource consuming. The current study tried to identify clinical predictors for pAF detected during long-term Holter ECG and clinical follow-up. METHODS: Patients with acute ischaemic stroke were prospectively investigated with an intensified algorithm to detect pAF (7-day Holter ECG, follow-up investigations after 90 days and 1 year). RESULTS: Two hundred and eighty-one patients were included, 44 of whom had to be excluded since they presented with permanent AF and another 13 patients had to be excluded due to other causes leaving 224 patients (mean age 68.5 years, 58.5% male). Twenty-nine (12.9%) patients could be identified to have pAF during prolonged Holter monitoring, an additional 13 (5.8%) after follow-up investigations. Multivariate analysis identified advanced age [odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01-1.08] as well as clinical symptoms >24 h (OR 5.17, 95% CI 1.73-15.48) and a history of coronary artery disease (OR 3.14, 95% CI 1.35-7.28) to be predictive for the detection of pAF. CONCLUSIONS: In acute stroke patients with advanced age, history of coronary artery disease and clinical symptoms >24 h, a prolonged Holter ECG monitoring and follow-up is warranted to identify pAF. This could increase the detection rate of patients requiring anticoagulation and may be able to reduce the risk of recurrent stroke in the case of successful anticoagulation of these patients.

Antibiotic use and risk of non-Hodgkin lymphomas.

Clinical case reports have suggested that specific bacterial infections are associated with certain non-Hodgkin lymphoma (NHL) subtypes. Epidemiological case-control studies have been conducted using antibiotics as a proxy for bacterial infections, but with inconclusive results. The aim of this study was, in a cohort design, based on the unique nationwide Danish registers, to investigate the association between use of antibiotics and the risk of NHL subtypes. On the basis of the Civil Registration System, we established a cohort of the entire adult (≥ 15 years) Danish population. Information on use of antibiotics came from the Danish Drug Prescription Registry and lymphoma diagnosis from the Danish Cancer Registry. Associations were assessed by adjusted rate ratios (RRs). In total, 13,602 patients were diagnosed with one of the NHL subtypes during 51.6 million person-years of follow-up (1995-2008). We observed positive associations between use of antibiotics and plasma cell myeloma [RR = 1.11, 95% confidence intervals (CIs) = 1.00-1.24], chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (RR = 1.32, 95% CI = 1.20-1.45), mantle cell lymphoma (MCL) (RR = 1.40, 95% CI = 1.04-1.88) and anaplastic large T-cell lymphoma (ALCL) (RR = 1.83, 95% CI = 1.00-3.36). Among these, the increased risk of CLL/SLL, MCL and ALCL, respectively, did not vary by years since use, and only the risk of CLL/SLL risk differed by number of prescriptions. While causality could not be established in our study, an intriguing positive long-term association between antibiotic use and CLL/SLL risk was observed. To what extent these findings indicate a role for bacteria in lymphoma pathogenesis requires further investigation.

N-(3-Cyanophenyl)-2-phenylacetamide, an effective inhibitor of morbillivirus-induced membrane fusion with low cytotoxicity.

Based on the structural similarity of viral fusion proteins within the family Paramyxoviridae, we tested recently described and newly synthesized acetanilide derivatives for their capacity to inhibit measles virus (MV)-, canine distemper virus (CDV)- and Nipah virus (NiV)-induced membrane fusion. We found that N-(3-cyanophenyl)-2-phenylacetamide (compound 1) has a high capacity to inhibit MV- and CDV-induced (IC(50) µM), but not NiV-induced, membrane fusion. This compound is of outstanding interest because it can be easily synthesized and its cytotoxicity is low [50 % cytotoxic concentration (CC(50)) ≥ 300 µM], leading to a CC(50)/IC(50) ratio of approximately 100. In addition, primary human peripheral blood lymphocytes and primary dog brain cell cultures (DBC) also tolerate high concentrations of compound 1. Infection of human PBMC with recombinant wild-type MV is inhibited by an IC(50) of approximately 20 µM. The cell-to-cell spread of recombinant wild-type CDV in persistently infected DBC can be nearly completely inhibited by compound 1 at 50 µM, indicating that the virus spread between brain cells is dependent on the activity of the viral fusion protein. Our findings demonstrate that this compound is a most applicable inhibitor of morbillivirus-induced membrane fusion in tissue culture experiments including highly sensitive primary cells.

Ongoing tuberculosis transmission to children in Greenland.

Inuit in the Arctic are experiencing an increase in tuberculosis cases, reaching levels in Greenland comparable to high-incidence countries. This prompted us to study the level of tuberculosis transmission to Greenlandic children. Specifically, we estimated the current prevalence of Mycobacterium tuberculosis infection (MTI) and the underlying annual risk of MTI. 2,231 Greenlandic school children aged 5-17 yrs (∼25% of the Greenlandic population in the relevant age group) were tested for MTI using the tuberculin skin test and the QuantiFERON®-TB Gold in-tube test. Subjects with dual-positive results were considered infected and subjects with dual-negative results uninfected. The children with discordant test results were classified as probably having MTI and analysed separately. 8.1% of the children had dual-positive test results. The annual risk of MTI was estimated as 0.80% (95% CI 0.67-0.92%) giving a cumulative risk at the 18th birthday of 13.4%. The annual risk of MTI varied substantially by ethnicity (0.87% in Inuit children, 0.02% in non-Inuit children; p<0.001) and by location (0.13% on the west coast, 1.68% on the south coast; p<0.001). M. tuberculosis transmission occurs at a very high level in Inuit children with pronounced geographic differences emphasising the need for immediate public health interventions.