Ulla B. Mogensen

Treatment with antipsychotics and the risk of diabetes in clinical practice.

BACKGROUND Treatment with antipsychotics seems to increase the risk of developing diabetes but the association is poorly characterised in clinical practice. AIMS To investigate and characterise the incidence of diabetes for people treated with antipsychotic medication in clinical practice. METHOD The study used the linkage of registers of all prescribed antipsychotics, antidiabetics and diagnoses of diabetes in Denmark during a period from 1996 to 2005 and identified all people treated with antipsychotics in Denmark and a random sample of about 30% of the total Danish population. RESULTS In total, 345,937 patients who purchased antipsychotics and 1,426,488 unexposed individuals were included in the study. Among the total population, 50,379 individuals subsequently developed incident diabetes. Compared with unexposed individuals, treatment with first- (rate ratio, RR = 1.53, 95% CI 1.49-1.56) as well as second-generation (RR = 1.32, 95% CI 1.22-1.42) antipsychotics was associated with increased risk of subsequent incident diabetes. The rate of incident diabetes varied substantially between individual second-generation antipsychotic drugs (olanzapine, risperidone clozapine compared with unexposed individuals: low to moderate rate ratio between 1.17 and 1.57; ziprasidone and sertindol: two or more times increased rate ratio; amisulpride, quetiapine and aripiprazole: no significantly increased rate ratio). For both first- and second-generation antipsychotics, the incidence of diabetes increased with the number of prescriptions. Additionally, the incidence of diabetes increased with the number of combined antipsychotic drugs. CONCLUSIONS In clinical practice, treatment with first- and second-generation antipsychotics is associated with an increased risk of developing incident diabetes with large differences between individual drugs. The risk increases with the duration of treatment and with polypharmacy of antipsychotic drugs.

Negative confounding by essential fatty acids in methylmercury neurotoxicity associations

BACKGROUND Methylmercury, a worldwide contaminant of fish and seafood, can cause adverse effects on the developing nervous system. However, long-chain n-3 polyunsaturated fatty acids in seafood provide beneficial effects on brain development. Negative confounding will likely result in underestimation of both mercury toxicity and nutrient benefits unless mutual adjustment is included in the analysis. METHODS We examined these associations in 176 Faroese children, in whom prenatal methylmercury exposure was assessed from mercury concentrations in cord blood and maternal hair. The relative concentrations of fatty acids were determined in cord serum phospholipids. Neuropsychological performance in verbal, motor, attention, spatial, and memory functions was assessed at 7 years of age. Multiple regression and structural equation models (SEMs) were carried out to determine the confounder-adjusted associations with methylmercury exposure. RESULTS A short delay recall (in percent change) in the California Verbal Learning Test (CVLT) was associated with a doubling of cord blood methylmercury (-18.9, 95% confidence interval [CI]=-36.3, -1.51). The association became stronger after the inclusion of fatty acid concentrations in the analysis (-22.0, 95% confidence interval [CI]=-39.4, -4.62). In structural equation models, poorer memory function (corresponding to a lower score in the learning trials and short delay recall in CVLT) was associated with a doubling of prenatal exposure to methylmercury after the inclusion of fatty acid concentrations in the analysis (-1.94, 95% CI=-3.39, -0.49). CONCLUSIONS Associations between prenatal exposure to methylmercury and neurobehavioral deficits in memory function at school age were strengthened after fatty acid adjustment, thus suggesting that n-3 fatty acids need to be included in analysis of similar studies to avoid underestimation of the associations with methylmercury exposure.

Breastfeeding as an Exposure Pathway for Perfluorinated Alkylates.

Perfluorinated alkylate substances (PFASs) are widely used and have resulted in human exposures worldwide. PFASs occur in breast milk, and the duration of breastfeeding is associated with serum-PFAS concentrations in children. To determine the time-dependent impact of this exposure pathway, we examined the serum concentrations of five major PFASs in a Faroese birth cohort at birth, and at ages 11, 18, and 60 months. Information about the childrens breastfeeding history was obtained from the mothers. The trajectory of serum-PFAS concentrations during months with and without breastfeeding was examined by linear mixed models that accounted for the correlations of the PFAS measurements for each child. The models were adjusted for confounders such as body size. The duration of exclusive breastfeeding was associated with increases of most PFAS concentrations by up to 30% per month, with lower increases during partial breast-feeding. In contrast to this main pattern, perfluorohexanesulfonate was not affected by breast-feeding. After cessation of breastfeeding, all serum concentrations decreased. This finding supports the evidence of breastfeeding being an important exposure pathway to some PFASs in infants.

Normal tension glaucoma and Alzheimer disease: comorbidity?

Purpose:  To investigate whether normal tension glaucoma (NTG) is associated with increased risk of developing dementia/Alzheimer disease (AD).

Cause-specific Mortality after Stroke: Relation to Age, Sex, Stroke Severity, and Risk Factors in a 10-Year Follow-up Study

We investigated cause-specific mortality in relation to age, sex, stroke severity, and cardiovascular risk factor profile in the Copenhagen Stroke Study cohort with 10 years of follow-up. In a Copenhagen community, all patients admitted to the hospital with stroke during 1992-1993 (n = 988) were registered on admission. Evaluation included stroke severity, computed tomography scan, and a cardiovascular risk profile. Cause of death within 10 years according to death certificate information was classified as stroke, heart/arterial disease, or nonvascular disease. Competing-risks analyses were performed by cause-specific Cox regression after multiple imputation of missing data, assuming that values were missing at random. Death was due to stroke in 310 patients (31%), to heart/arterial disease in 209 patients (21%), and to nonvascular diseases in 289 patients (29%); 180 patients were still alive after 10 years (18%). Stroke was the dominant cause of death during first year, with an absolute risk of 20.2% versus 5.2% for heart/arterial disease and 6.5% for nonvascular disease. The subsequent absolute risk of death per year was 2.8% for stroke, 4.5% for heart/arterial disease, and 5.2% for nonvascular disease. Death after stroke was associated with older age, male sex, greater stroke severity, and diabetes regardless of the cause of death. Previous stroke and hemorrhagic stroke were associated with death by stroke, ischemic heart disease was associated with death by heart/arterial disease and atrial fibrillation was associated with death by cardiovascular disease (stroke or heart/arterial disease). Hypertension, smoking, and alcohol consumption were not associated with cause-specific death.

Serum Vaccine Antibody Concentrations in Adolescents Exposed to Perfluorinated Compounds.

Background: Postnatal exposure to perfluorinated alkylate substances (PFASs) is associated with lower serum concentrations of specific antibodies against certain childhood vaccines at 7 y. Objectives: We prospectively followed a Faroese birth cohort to determine these associations at 13 y. Methods: In 516 subjects (79% of eligible cohort members) who were 13 years old, serum concentrations of PFASs and of antibodies against diphtheria and tetanus were measured and were compared with data from the previous examination at 7 y. Multiple regression analyses and structural equation models were applied to determine the association between postnatal PFAS exposures and antibody concentrations. Results: Serum concentrations of PFASs and antibodies generally declined from 7 y to 13 y. However, 68 subjects had visited the emergency room and had likely received a vaccination booster, and a total of 202 children showed higher vaccine antibody concentrations at 13 y than at 7 y. Therefore, separate analyses were conducted after exclusion of these two subgroups. Diphtheria antibody concentrations decreased at elevated PFAS concentrations at 13 y and 7 y; the associations were statistically significant for perfluorodecanoate (PFDA) at 7 y and for perfluorooctanoate (PFOA) at 13 y, both suggesting a decrease by ∼25% for each doubling of exposure. Structural equation models showed that a doubling in PFAS exposure at 7 y was associated with losses in diphtheria antibody concentrations at 13 y of 10–30% for the five PFASs. Few associations were observed for anti-tetanus concentrations. Conclusions: These results are in accord with previous findings of PFAS immunotoxicity at current exposure levels. https://doi.org/10.1289/EHP275

Leukocyte Profile in Peripheral Blood and Neutrophil-Lymphocyte Ratio in Hidradenitis Suppurativa: A Comparative Cross-Sectional Study of 462 Cases.

Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease. Increasing evidence suggests that HS involves dysfunctional immune responses in both the adaptive and the innate immune system. The recently proposed association of HS with metabolic syndrome may further add to the inflammatory state in HS. Objective: To investigate the status of inflammation and leukocyte profile in the peripheral blood of HS patients. Materials and Methods: Using a comparative cross-sectional study design, we investigated blood samples of high-sensitivity C-reactive protein (hs-CRP) and leukocyte profile in hospital-treated HS patients (HS-HOSP), self-reported population-based HS patients (HS-POP) and population controls. Results: Our study comprised 32 individuals in the HS-HOSP group, 430 in the HS-POP group, and 20,780 controls. The median hs-CRP for the HS-HOSP group was 5.1 mg/l (quartile range 2.6-8.2), 2.2 mg/l (1.0-4.3) for the HS-POP group and 1.3 mg/l (0.7-2.9) for the controls. An age-sex-adjusted analysis revealed a significantly higher hs-CRP for both HS groups compared to controls (p < 0.0001). When performing age-sex-adjusted analysis, both HS groups had significantly higher odds of leukocytosis when compared to controls with an odds ratio for the HS-HOSP group of 4.38 (95% CI = 2.18-8.80; p < 0.0001) and 1.95 (95% CI = 1.58-2.42; p < 0.0001) for the HS-POP group. The age-sex-adjusted leukocyte differential count yielded significantly higher neutrophil (p < 0.0001) and monocyte (p = 0.0014, p = 0.0004) levels in the HS groups compared with controls. Conclusion: The hs-CRP levels associated with HS appear to be intermediate (2.2-5.1 mg/l), implying systemic inflammation rather than infection. The peripheral blood leukocytosis in HS was dominated by neutrophils and monocytes.

A random forest approach for competing risks based on pseudo‐values

Random forest is a supervised learning method that combines many classification or regression trees for prediction. Here we describe an extension of the random forest method for building event risk prediction models in survival analysis with competing risks. In case of right-censored data, the event status at the prediction horizon is unknown for some subjects. We propose to replace the censored event status by a jackknife pseudo-value, and then to apply an implementation of random forests for uncensored data. Because the pseudo-responses take on values on a continuous scale, the node variance is chosen as split criterion for growing regression trees. In a simulation study, the pseudo split criterion is compared with the Gini split criterion when the latter is applied to the uncensored event status. To investigate the resulting pseudo random forest method for building risk prediction models, we analyze it in a simulation study of predictive performance where we compare it to Cox regression and random survival forest. The method is further illustrated in two real data sets.

Estimated exposures to perfluorinated compounds in infancy predict attenuated vaccine antibody concentrations at age 5-years

Abstract Perfluorinated alkylate substances (PFASs) are highly persistent and may cause immunotoxic effects. PFAS-associated attenuated antibody responses to childhood vaccines may be affected by PFAS exposures during infancy, where breastfeeding adds to PFAS exposures. Of 490 members of a Faroese birth cohort, 275 and 349 participated in clinical examinations and provided blood samples at ages 18 months and 5 years. PFAS concentrations were measured at birth and at the clinical examinations. Using information on duration of breastfeeding, serum-PFAS concentration profiles during infancy were estimated. As outcomes, serum concentrations of antibodies against tetanus and diphtheria vaccines were determined at age 5. Data from a previous cohort born eight years earlier were available for pooled analyses. Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure, while associations for serum concentrations at ages 18 months and 5 years were weaker. Modeling of serum-PFAS concentration showed levels for age 18 months that were similar to those measured. Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus. Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19–29% at age 5 for each doubling of the PFAS exposure in early infancy. These findings support the notion that the developing adaptive immune system is particularly vulnerable to immunotoxicity during infancy. This vulnerability appears to be the greatest during the first 6 months after birth, where PFAS exposures are affected by breast-feeding.

A Population- and Hospital-based Cross-sectional Study of Renal Function in Hidradenitis Suppurativa

The chronic inflammatory skin diseases hidradenitis suppurativa (HS) and psoriasis have been linked to cardiovascular risk factors and the latter has also been linked to possible renal dysfunction. Since basement membrane thinning in the skin of HS patients has been described, we speculated whether similar basement membrane defects might occur in renal tissue. Our objective was to investigate a possible association between HS and renal dysfunction. We performed a hospital and population-based cross-sectional study using estimated Glomerular-Filtration-Rate (eGFR) to assess renal function. Thirty-two hospital individuals with HS, 430 population individuals with HS, and 20,780 population individuals without HS were (controls) identified. The age-, sex-, smoking-, BMI-, hypertension- and diabetes-adjusted analysis revealed a statistically significant higher eGFR for the hospital group with HS and a mean difference in eGFR of 6.81 (1.27-12.35) ml/min/1.73 m2 between the hospital group with HS and the population group without HS. The observed higher eGFR in the hospital group with HS indicates a possible association of HS and renal dysfunction.