Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10.

The effects of one genetic factor upon Parkinson's disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the 'missing heritability' of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson's Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65-1.95, p = 2.7 × 10-43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.

Cost-effectiveness of surgical treatment compared to medical treatment in patients with drug-refractory epilepsy: A systematic review.

BACKGROUND AND PURPOSE: Approximately 30% of epilepsy patients develop a drug-refractory epilepsy, that is, seizures cannot be controlled with antiepileptic drugs. Surgery has been evaluated as an effective but costly form of treatment. The aim of this systematic review is to synthesize the available evidence on the cost-effectiveness of surgical treatment compared to medical treatment for these patients. METHOD: A systematic literature search was performed in MEDLINE, Embase, PsycINFO, Cochrane Library and the National Health Service Economic Evaluation Database until September 2022. Title, abstract and full-text screening were conducted by two researchers. Original studies published in English or German analyzing the cost-effectiveness of surgical compared to medical treatment were included. Study characteristics, effectiveness measures, costs and incremental cost-effectiveness ratios (ICERs) were extracted. The quality of studies was assessed using the Drummond checklist. RESULTS: Fourteen studies were included. Most studies evaluated surgery as cost-effective. The ICER per patient seizure free ranged from dominant to purchasing power parity US dollars (PPP-USD) 479,275. The ICER per 1% seizure reduction ranged from PPP-USD 227 to PPP-USD 342. The ICER per year without seizures was PPP-USD 4202 and the ICER per quality-adjusted life-year ranged from dominant to PPP-USD 90,874. The studies varied greatly in their methodology and time horizon. CONCLUSION: Surgical treatment is cost-effective compared to medical treatment, especially when a lifetime horizon is adopted. It is concluded that all disease-specific costs should be considered over a long period when assessing the cost-effectiveness of epilepsy treatment. From an economic perspective, efforts should be made to improve access to surgical treatment for patients with drug-refractory epilepsy.

Cognitive parameters can predict change of walking performance in advanced Parkinson's disease - Chances and limits of early rehabilitation.

Introduction: Links between cognition and walking performance in patients with Parkinson's disease (PD), which both decline with disease progression, are well known. There is lack of knowledge regarding the predictive value of cognition for changes in walking performance after individualized therapy. The aim of this study is to identify relevant predictive cognitive and affective parameters, measurable in daily clinical routines, for change in quantitative walking performance after early geriatric rehabilitation. Methods: Forty-seven acutely hospitalized patients with advanced PD were assessed at baseline (T1) and at the end (T2) of a 2-week early rehabilitative geriatric complex treatment (ERGCT). Global cognitive performance (Montreal Cognitive Assessment, MoCA), EF and divided attention (Trail Making Test B minus A, delta TMT), depressive symptoms, and fear of falling were assessed at T1. Change in walking performance was determined by the difference in quantitative walking parameters extracted from a sensor-based movement analysis over 20 m straight walking in single (ST, fast and normal pace) and dual task (DT, with secondary cognitive, respectively, motor task) conditions between T1 and T2. Bayesian regression (using Bayes Factor BF10) and multiple linear regression models were used to determine the association of non-motor characteristics for change in walking performance. Results: Under ST, there was moderate evidence (BF10 = 7.8, respectively, BF10 = 4.4) that lower performance in the ∆TMT at baseline is associated with lower reduction of step time asymmetry after treatment (R 2 adj = 0.26, p ≤ 0.008, respectively, R 2 adj = 0.18, p ≤ 0.009). Under DT walking-cognitive, there was strong evidence (BF10 = 29.9, respectively, BF10 = 27.9) that lower performance in the ∆TMT is associated with more reduced stride time and double limb support (R 2 adj = 0.62, p ≤ 0.002, respectively, R 2 adj = 0.51, p ≤ 0.009). There was moderate evidence (BF10 = 5.1) that a higher MoCA total score was associated with increased gait speed after treatment (R 2 adj = 0.30, p ≤ 0.02). Discussion: Our results indicate that the effect of ERGT on change in walking performance is limited for patients with deficits in EF and divided attention. However, these patients also seem to walk more cautiously after treatment in walking situations with additional cognitive demand. Therefore, future development of individualized treatment algorithms is required, which address individual needs of these vulnerable patients.

Genotype imputation in case-only studies of gene-environment interaction: validity and power.

Case-only (CO) studies are a powerful means to uncover gene-environment (G × E) interactions for complex human diseases. Moreover, such studies may in principle also draw upon genotype imputation to increase statistical power even further. However, genotype imputation usually employs healthy controls such as the Haplotype Reference Consortium (HRC) data as an imputation base, which may systematically perturb CO studies in genomic regions with main effects upon disease risk. Using genotype data from 719 German Crohn Disease (CD) patients, we investigated the level of imputation accuracy achievable for single nucleotide polymorphisms (SNPs) with or without a genetic main effect, and with varying minor allele frequency (MAF). Genotypes were imputed from neighbouring SNPs at different levels of linkage disequilibrium (LD) to the target SNP using the HRC data as an imputation base. Comparison of the true and imputed genotypes revealed lower imputation accuracy for SNPs with strong main effects. We also simulated different levels of G × E interaction to evaluate the potential loss of statistical validity and power incurred by the use of imputed genotypes. Simulations under the null hypothesis revealed that genotype imputation does not inflate the type I error rate of CO studies of G × E. However, the statistical power was found to be reduced by imputation, particularly for SNPs with low MAF, and a gradual loss of statistical power resulted when the level of LD to the SNPs driving the imputation decreased. Our study thus highlights that genotype imputation should be employed with great care in CO studies of G × E interaction.

Case-only analysis of gene-gene interactions in inflammatory bowel disease.

BACKGROUND: Gene-gene interactions (G × G) potentially play a role in the etiology of complex human diseases, including inflammatory bowel disease (IBD), and may partially explain their 'missing heritability'. METHODS: Using the largest genotype dataset available for IBD (16,636 Crohn's disease (CD) and 12,888 ulcerative colitis (UC) cases) we analyzed G × G with the powerful case-only (CO) design. We studied 169 single nucleotide polymorphisms (SNPs) for CD (156 for UC), previously shown to be associated with the respective diseases. To ensure the validity of the CO design, we confined our analysis to pairs of unlinked SNPs. We used principal component analysis at the center level to adjust for possible causes of genotypic association other than G × G, such as population stratification and genotyping batch effects. Results from center-wise logistic regression analyses were combined by a random effects meta-analysis. RESULTS: A number of nominally significant (p < .05) G × G interactions were observed, but none of these withstood the Bonferroni multiple testing correction. However, one SNP pair, comprising rs26528 in the IL27 gene and rs9297145 in the KPNA7 gene region was characterized by an interaction odds ratio of 1.18 (95% CI: 1.10-1.27) for CD and a p-value of 7.75 × 10-6. Owing to the concurrent role of the IL27 and KPNA7 genes in NF-κB signaling, a master regulator of pro- and anti-inflammatory processes in IBD, the observed interaction also has biological plausibility. CONCLUSIONS: We were able to exemplify the utility of the CO design for analyzing G × G, but had to recognize that such interactions are probably scarce for IBD.

Cleaning and Conditioning of Contaminated Core Build-Up Material before Adhesive Bonding.

The objective of this study was to evaluate the effects of different cleaning and conditioning procedures after contamination on the tensile bond strength (TBS) of a luting resin to a core build-up composite resin. Specimens (n = 384) made of a core build-up material were stored for 3 weeks in 37 °C water. Half of the specimens were contaminated with saliva and a disclosing silicone and then cleaned either using phosphoric acid, a pumice suspension, air-abrasion with alumina or polishing powder. Surface conditioning was performed by either using a dentin adhesive, a silane containing primer or a composite resin primer, which resulted in 24 unique combinations of 16 specimens per group. Before measuring TBS, half of the specimens of each group were stored in 37 °C water for 3d or were artificially aged for 150 days. Results show that cleaning with pumice or air-abrasion are superior methods compared to using a polishing powder or phosphoric acid. Silane is an inferior conditioning agent compared to composite or dentin primers. Ideally, after contamination, bonding surfaces should be cleaned with a pumice suspension and conditioned with a dentin adhesive. Those surfaces could also be cleaned and conditioned with air-abrasion with alumina particles and a composite resin primer.