Clostridium difficile infection and risk of Parkinson's disease: a Swedish population-based cohort study.

BACKGROUND AND PURPOSE: Gastrointestinal inflammation has been implicated in Parkinson's disease (PD). The aim of this study was to examine whether individuals with a history of Clostridium difficile infection (CDI) are at elevated risk of PD. METHODS: We performed a population-based cohort study using Swedish national register data. Adults aged ≥35 years were identified from the Swedish Population and Housing Census 1990 and followed during the period 1997-2013. Diagnoses of CDI and PD were extracted from the National Patient Register. Associations of CDI history with PD risk were estimated using Cox proportional hazards regression. We also explored whether the association differed by the source of CDI diagnosis (inpatient vs. outpatient), presence of recurrent infections, and pre-infection use of antibiotics. RESULTS: Amongst the study population (N = 4 670 423), 34 868 (0.75%) had a history of CDI. A total of 165 and 47 035 incident PD cases were identified from individuals with and without CDI history, respectively. Across the entire follow-up, a 16% elevation of PD risk was observed among the CDI group [hazard ratio 1.16, 95% confidence interval (CI)1.00-1.36], which was mainly driven by increased PD risk within the first 2 years after CDI diagnosis (hazard ratio 1.38, 95% CI 1.12-1.69). In longer follow-up, CDI was not associated with subsequent PD occurrence. This temporal pattern of CDI-PD associations was generally observed across all CDI subgroups. CONCLUSIONS: Clostridium difficile may be associated with an increased short-term PD risk, but this might be explained by reverse causation and/or surveillance bias. Our results do not imply that CDI history affects long-term PD risk.

Timing of two versus three doses of quadrivalent HPV vaccine and associated effectiveness against condyloma in Sweden: a nationwide cohort study.

OBJECTIVE: To assess incidence of condyloma after two doses of quadrivalent human papillomavirus (qHPV) vaccine, by time since first vaccine dose, in girls and women initiating vaccination before age 20 years. DESIGN: Register-based nationwide open cohort study. SETTING: Sweden. PARTICIPANTS: Girls and women initiating qHPV vaccination before age 20 years between 2006 and 2012. The study cohort included 264 498 girls, of whom 72 042 had received two doses of qHPV vaccine and 185 456 had received all three doses. MAIN OUTCOME MEASURE: Incidence rate ratios (IRRs) of condyloma estimated by time between first and second doses of qHPV in months (m) and age at vaccination, adjusted for attained age. RESULTS: For girls first vaccinated with two doses before the age of 17 years, the IRR of condyloma for 0-3 months between the first and second doses was 1.96 (95% CI 1.43 to 2.68) as compared with the standard three-dose schedule. The IRRs were 1.27 (95% CI 0.63 to 2.58) and 4.36 (95% CI 2.05 to 9.28) after receipt of two doses with 4-7 months and 8+ months between doses, respectively. For women first vaccinated after the age of 17 years, vaccination with two doses of qHPV vaccine and 0-3 months between doses was associated with an IRR of 2.12 (95% CI 1.62 to 2.77). For an interval of 4-7 months between doses, the IRR did not statistically significantly differ to the standard three-dose schedule (IRR=0.81, 95% CI 0.36 to 1.84). For women with 8+ months between dose 1 and dose 2 the IRR was 3.16 (95% CI 1.40 to 7.14). CONCLUSION: A two-dose schedule for qHPV vaccine with 4-7 months between the first and second doses may be as effective against condyloma in girls and women initiating vaccination under 20 years as a three-dose schedule. Results from this nationwide study support immunogenicity data from clinical trials.

Genetic susceptibility to cardiovascular disease and risk of dementia.

Several studies have shown cardiovascular disease (CVD) to be associated with dementia, but it is not clear whether CVD per se increases the risk of dementia or whether the association is due to shared risk factors. We tested how a genetic risk score (GRS) for coronary artery disease (CAD) affects dementia risk after CVD in 13 231 Swedish twins. We also utilized summarized genome-wide association data to study genetic overlap between CAD and Alzheimer´s disease (AD), and additionally between shared risk factors and each disease. There was no direct effect of a CAD GRS on dementia (hazard ratio 0.99, 95% confidence interval (CI): 0.98-1.01). However, the GRS for CAD modified the association between CVD and dementia within 3 years of CVD diagnosis, ranging from a hazard ratio of 1.59 (95% CI: 1.05-2.41) in the first GRS quartile to 1.91 (95% CI: 1.28-2.86) in the fourth GRS quartile. Using summary statistics, we found no genetic overlap between CAD and AD. We did, however, find that both AD and CAD share a significant genetic overlap with lipids, but that the overlap arose from clearly distinct gene clusters. In conclusion, genetic susceptibility to CAD was found to modify the association between CVD and dementia, most likely through associations with shared risk factors.

Short telomere length is associated with impaired cognitive performance in European ancestry cohorts.

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (ß=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (ß=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (ß=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (ß=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (ß=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (ß=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (ß=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

Self-sampling for analysis of respiratory viruses in a large-scale epidemiological study in Sweden.

Viral diagnosis of respiratory tract infections has so far required sampling by health professionals,hampering large-scale epidemiological studies of virus-specific disease outcomes. As part of a population-based, prospective study of work-related risk factors for transmission of viral infections (SWEDE-I), we developed a scheme for self-sampling with nasal swabs. Random selection from the gainfully employed population of a medium-sized town in central Sweden resulted in a study cohort of 2,237 men and women aged 25 to 63 years. From September 2011 through May 2012, the cohort reported all instances of respiratory tract infection or gastroenteritis and participants concomitantly sent self-sampled nasal swabs for analysis using regular mail. Diagnosis of 14 viruses was performed. A total of 1,843 samples were received. The week-wise average delay between disease on set and arrival of the specimens at the laboratory varied between four and six days, and the corresponding median delay was between 3.5 and six days. In line with previous community-based studies, picorna- and coronaviruses dominated in specimens obtained from the self-sampling scheme. The results of self-sampling were contrasted to those from contemporaneous routine clinical sampling, on the same age group, in the adjacent Stockholm county. Although higher proportions of positive samples for respiratory syncytial virus and influenza were observed in the clinical sampling scheme, estimations of seasonality for influenza A and picornaviruses derived from both schemes were similar. Our findings show that nasal self-sampling is feasible in large-scale surveillance of respiratory infections and opens new prospects for population based,virologically verified research on virus spread,burden of disease, and effects of environmental factors or interventions.

Mammographic density and molecular subtypes of breast cancer.

BACKGROUND: Gene expression profiling has led to a subclassification of breast cancers independent of established clinical parameters, such as the Sorlie-Perou subtypes. Mammographic density (MD) is one of the strongest risk factors for breast cancer, but it is unknown if MD is associated with molecular subtypes of this carcinoma. METHODS: We investigated whether MD was associated with breast cancer subtypes in 110 women with breast cancer, operated in Stockholm, Sweden, during 1994 to 1996. Subtypes were defined using expression data from HGU133A+B chips. The MD of the unaffected breast was measured using the Cumulus software. We used multinomial logistic models to investigate the relationship between MD and Sorlie-Perou subtypes. RESULTS: Although the distribution of molecular subtypes differed in women with high vs low MD, this was statistically non-significant (P=0.249), and further analyses revealed no association between the MD and Sorlie-Perou subtypes as a whole, nor with individual subtypes. CONCLUSION: These findings suggest that although MD is one of the strongest risk factors for breast cancer, it does not seem to be differentially associated with breast cancer molecular subtypes. However, larger studies with more comprehensive covariate information are needed to confirm these results.

Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia.

Glucocorticoids (GCs) induce apoptosis in lymphoid lineage cells and are therefore used in the therapy of acute lymphoblastic leukemia (ALL) and related malignancies. MicroRNAs (miRNAs) and the related mirtrons are ~22 nucleotide RNAs derived from polymerase-II transcripts and implicated in the control of essential biological functions, including apoptosis. Whether GCs regulate miRNA-encoding transcription units is unknown. We investigated miRNA/mirtron expression and GC regulation in 8 leukemia/lymphoma in vitro models and 13 ALL children undergoing systemic GC monotherapy using a combination of expression profiling techniques, real time reverse transcription (RT)-PCR and northern blotting to detect mature miRNAs and/or their precursors. We found that mature miRNA regulations can be inferred from expression data of their host genes. Although a simple miRNA-initiated canonical pathway to GC-induced apoptosis or cell cycle arrest did not emerge, we identified several miRNAs/mirtrons that were regulated by GC in patients and cell lines, including the myeloid-specific miR-223 and the apoptosis and cell cycle arrest-inducing miR15 ~ 16 clusters. In an in vitro model, overexpression of miR15b ~ 16 mimics increased and silencing by miR15b ~ 16 inhibitors decreased GC sensitivity. Thus, the observed complex changes in miRNA/mirtron expression during GC treatment might contribute to the anti-leukemic GC effects in a cell context-dependent manner.