Mosaic deletions in X-linked dystonia-parkinsonism influence repeat stability and disease onset

Background: While multiple genetic causes of movement disorders have been identified in the past decade, modifying factors of disease expression are still largely unknown for most conditions. X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative disease caused by a SINE-VNTR-Alu (SVA)-type retrotransposon insertion that contains a hexanucleotide repeat within an intron of the TAF1 gene. To date, four putative genetic modifiers explain about 65% of variance in age at onset in XDP. However, additional genetic modifiers are conceivably at play in XDP and may include mismatches of the SVA hexanucleotide repeat motif. We aim to identify additional genetic modifiers of XDP expressivity and age at onset (AAO). Methods: Third-generation sequencing of PCR amplicons from XDP patients (n=202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment were used to confirm the presence of identified repeat mismatches. Results: An increased frequency of deletions at the beginning of the hexanucleotide repeat (CCCTCT)n domain was found. Specifically, three deletions at positions 11, 14, and 17 of the TAF1 SVA repeat motif of somatic mosaic origins were detected in different combinations. The most common one was three deletions (1-2-3) at a median frequency 0.425 (IQR:0.42-0.43) and deletions within positions 11 and 14 (1-2-wt) at a median frequency 0.128 (IQR:0.12-0.13). The frequency of deletions at positions 11 and 14 correlated with repeat number (r=-0.48, p=9.5x10-13) and AAO (r=0.34, p=9.5x10-7). The association with AAO still stands when including other modifier genotypes (MSH3 and PMS2) in a regression model. However, the association dissipates when including repeat numbers. Conclusion: We present a novel mosaic repeat motif deletion within the hexanucleotide repeat (CCCTCT)n domain of TAF1 SVA. Our study illustrates: 1) the importance of somatic mosaic genotypes; 2) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; 3) that these variations may remain undetected without assessment of single molecules.

Factors Influencing Protective Behaviors for Dental Radiation Exposure among Female Korean Dental Hygienists Using Health Belief Model

This study aimed to identify the associated factors for protective behaviors for dental radiation exposure (PBDRE) among dental hygienists using the health belief model (HBM). The HBM, which is composed of perceived susceptibility, perceived seriousness, perceived benefits, perceived barriers, and cues to action, explains preventive behavior. In this study, self-efficacy and modifying factors were additionally applied to the HBM. The subjects of the study were 204 dental hygienists who were working at hospitals or clinics in Korea. An online survey was conducted to measure PBDRE-related factors based on the HBM and self-efficacy. The collected data were analyzed using frequency analysis, t-tests, ANOVA, Pearson’s correlation analysis, and hierarchical multiple regression analysis. Regarding modifying factors, performance was found to be high when protection facilities were sufficient (β = 0.24, p < 0.001) and low when radiation education was not received (β = −0.16, p < 0.05). Among the HBM factors, cues to action for PBDRE (β = 0.28, p < 0.001) was the most influential factor in the performance of PBDRE, and the effect of its perceived benefits on radiation exposure was also high (β = 0.17, p < 0.001). Regarding the performance of PBDRE according to the HBM, providing education programs on protection can stimulate appropriate cues to action to perform PBDRE. In addition, if the benefits of PBDRE are highlighted, the performance of PBDRE by dental hygienists is increased.

The Influence of Cardiovascular Risk Factors and Hypogonadism on Cardiac Outcomes in an Aging Population of Beta-Thalassemia Patients

Beta-thalassemia major (β-TM) is a hereditary genetic disease worsened by many comorbidities due to transfusion-related iron despite chelation therapy. Since there has recently been an increase in life expectancy of patients to up to 50 years old, which influences the prevalence of these diseases and the time span for traditional cardiovascular risk factors to play their role, this study aims to evaluate their distribution and prevalence in a population of thalassemia major patients and their relationship with observed cardiovascular events and potential modifying factors. One hundred and fifty-nine β-TM patients with at least 15 years of follow-up were included in this study. The mean age was 40.9 ± 8.4 years; 28% had diabetes mellitus and 62% had hypogonadism. The cardiovascular risk assessed using algorithms (CUORE and Pooled Cohort Risk Equation—PCRE) was low, but 3.8% of patients had at least one episode of heart failure, 35.9% showed early signs of heart failure, 22% received a diagnosis of diastolic dysfunction, and 21.4% showed supraventricular arrhythmias. Hypogonadism was shown to be related to the occurrence of cardiovascular events. The chronic accumulation of iron in the heart and the specific metabolic profile, mainly observed in patients with hypogonadism, allows us to define β-TM as a condition with a high level of cardiovascular risk from many points of view (iron-related myopathy, atherosclerosis and arrhythmias), which requires better stratification tools and a specific follow-up program.

Deciphering DNA Methylation in HIV Infection

With approximately 38 million people living with HIV/AIDS globally, and a further 1.5 million new global infections per year, it is imperative that we advance our understanding of all factors contributing to HIV infection. While most studies have focused on the influence of host genetic factors on HIV pathogenesis, epigenetic factors are gaining attention. Epigenetics involves alterations in gene expression without altering the DNA sequence. DNA methylation is a critical epigenetic mechanism that influences both viral and host factors. This review has five focal points, which examines (i) fluctuations in the expression of methylation modifying factors upon HIV infection (ii) the effect of DNA methylation on HIV viral genes and (iii) host genome (iv) inferences from other infectious and non-communicable diseases, we provide a list of HIV-associated host genes that are regulated by methylation in other disease models (v) the potential of DNA methylation as an epi-therapeutic strategy and biomarker. DNA methylation has also been shown to serve as a robust therapeutic strategy and precision medicine biomarker against diseases such as cancer and autoimmune conditions. Despite new drugs being discovered for HIV, drug resistance is a problem in high disease burden settings such as Sub-Saharan Africa. Furthermore, genetic therapies that are under investigation are irreversible and may have off target effects. Alternative therapies that are nongenetic are essential. In this review, we discuss the potential role of DNA methylation as a novel therapeutic intervention against HIV.

Arterial Stiffness and Age Moderate the Association Between Physical Activity and Cognition in Older Adults

Background Evidence supports that time spent on physical activity has beneficial effects on cognition in older adults. Nevertheless, this beneficial effect is likely to change in function of individual modifying factors like age and level of arterial stiffness. This study aims to reveal whether arterial stiffness and age modulate the positive impact of physical activity on cognition by developing a double moderation model. Methods 110 healthy older adults aged 60 to 75 years old were examined for arterial stiffness (carotid-femoral Pulse Wave Velocity [cf-PWV]), global cognition (composite score of Montreal Cognitive Assessment, and Mini-Mental State Examination), and self-reported physical activity (PACED diary). Using PROCESS macro for SPSS, we evaluated if cf-PWV (moderator 1), and age (moderator 2) moderate the relationship between physical activity (X) and global cognition (Y). The threshold for high stiffness was set at 8.5 m/s based on previous studies that reported this cut-off more appropriate for classifying cerebrovascular risk groups. Results The interaction of arterial stiffness x age moderated the effect of physical activity on global cognition (β=-.89, SE=.42, p=.037) (Model: R2=.15, p=.018). Physical activity had a positive effect on cognition in younger-older adults (aged 60 to 68.5 years) with cf-PWV&gt;8.5 m/s (β=.57, SE=.222, p=.011, 95% CI.133 to 1.014) and on older-older adults (aged 68.6 to 75 years) with cf-PWV&lt;8.5 m/s (β=.49, SE=.190, p=.010, 95% CI=.116 to .869). Conclusions Identifying the right age groups and arterial stiffness levels at which physical activity can have beneficial effects on cognition is a key step in providing tailored behavioral interventions.

Deoxygenation of the eastern Indonesian waters and its variability

Long-term ocean deoxygenation could lead to decline biological productivity and alter biogeochemical cycles. Ocean warming contributions to ocean deoxygenation are reasonably understood, however, there is a challenge to reveal the gaps about other modifying factors to explain different regional patterns and predicts the condition in the coming century. This study aimed to identify the deoxygenation areas in the eastern Indonesian waters, understand the variability of physical and chemical parameters as the deoxygenation drivers, and investigate the correlation between parameters. In-situ and satellite-derived data from 1995 to 2020 were analyzed with statistical methods and remote sensing techniques to enhance deoxygenation measures in higher spatial and temporal resolutions. Our findings revealed that significant deoxygenation was detected around the Arafura Sea. The oxygen minimum zone extended at 133.5° – 136.8° E in the depth of 350 – 1,000 meters, with less than 20 mmol/m3 of dissolved oxygen concentration. Nitrate, phosphate, and temperature were identified to have a strong reversed relationship with the oxygen concentration in the study area. This study also developed multiple regression model algorithms to estimate the oxygen concentration in specified depths.

Imaging as a Selection Tool for Thrombectomy in Acute Ischemic Stroke

Large vessel occlusion (LVO) stroke represents a stroke subset associated with the highest morbidity and mortality. Multiple prospective randomized trials have shown that thrombectomy, alone or in conjunction with IV thrombolysis, is highly effective in reestablishing cerebral perfusion and improving clinical outcomes. In unselected patients and especially in patients with poor collaterals, the benefit of reperfusion therapy is exquisitely time sensitive; the earlier thrombectomy is started, the lower the likelihood of disability or death. Understanding both the pathophysiologic underpinnings and the modifying factors of this strong time-to-treatment effect demonstrated in numerous randomized clinical trials is important for implementation of intrahospital workflow measures to maximize time efficiency of thrombectomy. Reducing delays in reperfusion therapy initiation has become a priority in acute stroke care, and therefore a thorough understanding of the main systems-based factors responsible for these delays is critical. Because the time spent evaluating the patient in the emergency department, which typically includes neuroimaging studies performed in scanners remote from the angiography suite, represents the main source of delays in thrombectomy initiation, the direct to angiography (DTA) model has emerged as a means to substantially reduce treatment times and is being instituted at an increasing number of thrombectomy centers across the world. The aim of this report is to introduce DTA as an emerging stroke care paradigm for patients with suspicion of LVO stroke, review results from studies evaluating its feasibility and impact on outcomes, describe current barriers to its more widespread adoption, and propose potential solutions to overcoming these barriers.

Genetic Risk Variants for Class Switching Recombination Defects in Ataxia-Telangiectasia Patients

Background Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. A-T patients manifest considerable variability in clinical and immunological features, suggesting the presence of genetic modifying factors. A striking heterogeneity has been observed in class switching recombination (CSR) in A-T patients which cannot be explained by the severity of ATM mutations. Methods To investigate the cause of variable CSR in A-T patients, we applied whole-exome sequencing (WES) in 20 A-T patients consisting of 10 cases with CSR defect (CSR-D) and 10 controls with normal CSR (CSR-N). Comparative analyses on modifier variants found in the exomes of these two groups of patients were performed. Results For the first time, we identified some variants in the exomes of the CSR-D group that were significantly associated with antigen processing and presentation pathway. Moreover, in this group of patients, the variants in four genes involved in DNA double-strand breaks (DSB) repair signaling, in particular, XRCC3 were observed, suggesting an association with CSR defect. Conclusion Additional impact of certain variants, along with ATM mutations, may explain the heterogeneity in CSR defect phenotype among A-T patients. It can be concluded that genetic modulators play an important role in the course of A-T disease and its clinical severity.

Patient doses in endovascular and hybrid revascularization of aortoiliac segment

Objectives: Constantly increasing number of procedures performed – endovascular or hybrid in patients with aortoiliac occlusive disease during the last decades finds its explanation in the lower morbidity and mortality rates, compared to bypass surgery. The purpose of the current survey was to estimate patients’ radiation exposure in aortoiliac segment after endovascular or hybrid revascularization and to study the main factors which have direct contribution. Methods: A retrospective study of 285 procedures conducted with the help of a mobile C-arm system in 223 patients was performed. Procedures were grouped according to criteria such as: type of intervention, vascular access, level of complexity and operating team. Different analyses were performed within the groups and dose values. Results: The median values of kerma–air product (KAP), the number of series and the peak skin dose (PSD) significantly increase with the increasing number of vascular accesses: for one access (16.68 Gy.cm2, 6 and 336 mGy), for two (56.93 Gy.cm2, 11 and 545 mGy), and for three (102.28 Gy.cm2, 15 and 781 mGy). Significant dependence was observed in the case of single access site between the type of access and the dose values: hybrid and retrograde common femoral artery/superficial femoral artery (CFA/SFA) endovascular accesses, 10.06 Gy.cm2/301 mGy and 13.23 Gy.cm2/318 mGy respectively, in contrast with the contralateral CFA and left brachial access, 33 Gy.cm2/421 mGy and 38.33 Gy.cm2/448 mGy respectively. Conclusion: The results demonstrate that the most important factors increasing the dose values are number and type of vascular accesses, followed by the combination and number of implanted stents with the complexity of the procedure. The PSD values for a single procedure were between 2 and 12 times lower than those IAEA proposed as trigger levels for radiation-induced erythema. This study shows that trigger levels were not reached even for patients with repeated procedures in the same segment in 1-year period. Advances in knowledge: The study gives important understanding and clarity on the growing awareness for dose-modifying factors during endovascular and hybrid revascularization of aortoiliac segment.