Genetic Identification of Homozygous Familial Hypercholesterolemia by Long-Read Sequencing Among Patients With Clinically Diagnosed Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma low-density lipoprotein cholesterol and accelerated atherosclerosis. Accurate identification of patients with HoFH is essential as they may be eligible for specialized treatments. We hypothesized that a subset of patients with clinically diagnosed heterozygous FH (HeFH) may in fact have HoFH, and this could be identified by genetic diagnosis. METHODS: We recruited patients with a clinical diagnosis of HeFH based on a Dutch Lipid Clinic Network score ≥6 and no secondary cause of hypercholesterolemia. We performed targeted next-generation sequencing of the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein receptor adapter protein 1 (LDLRAP1) genes, followed by long-read sequencing of the LDLR gene in patients with >1 pathogenic LDLR variant. We examined lipid levels and cardiovascular events. RESULTS: Among 705 patients with clinically diagnosed HeFH, we identified a single pathogenic variant in 300 (42.6%) and >1 pathogenic variant in the LDLR gene in 11 patients (1.6%). We established a genetic diagnosis of HoFH in 6 (0.9%) patients (3 true homozygotes and 3 compound heterozygotes). The mean baseline low-density lipoprotein cholesterol and prevalence of premature cardiovascular disease of patients with genetically identified HoFH was significantly higher than patients with HeFH. CONCLUSIONS: In a cohort of patients with clinically diagnosed HeFH, genetic testing including long-read sequencing revealed that 0.9% had HoFH. These patients tended to have a more severe clinical phenotype. Genetic testing of patients with clinical FH may identify patients with HoFH that had eluded clinical diagnosis.

Sex Differences in Subsequent Falls and Falls Risk: A Prospective Cohort Study in Older Adults.

BACKGROUND: Sex differences for subsequent falls and falls risk factors in community-dwelling older adults who have fallen are unknown. Our aim was to: (1) compare the number of falls between sexes, (2) identify modifiable falls risk factors, and (3) explore the interaction of sex on falls risk factors in older adults who fall. METHODS: Four hundred sixty-two community dwellers seeking medical attention after an index fall were recruited from the Vancouver Falls Prevention Clinic and participated in this 12-month prospective cohort study. Ninety-six participants were part of a randomized controlled trial of exercise. Falls were tracked with monthly falls calendars. Demographics, falls risk measures, and the number of subsequent falls were compared between sexes. A principal component analysis (PCA) was employed to reduce the falls risk measures to a smaller set of factors. The PCA factors were used in negative binomial regression models to predict the number of subsequent falls. Age, exposure time (i.e., number of falls monitoring days), and prescribed exercise (yes/no) were used as covariates, and sex (male/female) and PCA factors were used as main effects. The interaction of sex by PCA factor was then included. RESULTS: Males fell more over 12 months (males: 2.80 ± 6.86 falls; females: 1.25 ± 2.63 falls) than females, and poorer executive function predicted falls in males. Four PCA factors were defined - impaired cognition and mobility, low mood and self-efficacy, mobility resilience, and perceived poor health - each predicted the number of falls. The sex by mobility resilience interaction suggested that mobility resilience was less protective of falls in males. CONCLUSION: Modifiable risk factors related to cognition, physical function, psychological wellbeing, and health status predicted subsequent falls. In males, better mobility was not as protective of falls compared with females. This may be due to males' poorer executive function, contributing to decreased judgement or slowed decision-making during mobility. These results may inform efficacious sex-specific falls prevention strategies.

Exercise, Processing Speed, and Subsequent Falls: A Secondary Analysis of a 12-Month Randomized Controlled Trial.

BACKGROUND: Strength and balance retraining exercises reduce the rate of subsequent falls in community-dwelling older adults who have previously fallen. Exercise can also improve cognitive function, including processing speed. Given processing speed predicts subsequent falls, we aimed to determine whether improved processing speed mediated the effects of the Otago Exercise Program on the rate of subsequent: (i) total falls, (ii) non-injurious falls, (iii) moderate injurious falls, and (iv) serious injurious falls. METHOD: A secondary complete case analysis of a 12-month, single-blind, randomized clinical trial among 256 of 344 adults aged at least 70 years who fell in the previous 12 months. Participants were randomized 1:1 to receive usual care plus the Otago Exercise Program (n = 123) or usual care (n = 133), consisting of fall prevention care provided by a geriatrician. The primary outcome was self-reported number of falls over 12 months (ie, rate of falls). Processing speed was assessed at baseline and at 12 months by the Digit Symbol Substitution Test (DSST). Causal mediation analyses were conducted using quasi-Bayesian estimates and 95% confidence intervals. RESULTS: Exercise significantly reduced the rate of subsequent moderate injurious falls (IRR = 0.49; 95% CI: 0.31, 0.77; p = .002) and improved processing speed (estimated mean difference: 1.16 points; 95% CI: 0.11, 2.21). Improved DSST mediated the effect of exercise on the rate of subsequent moderate injurious falls (estimate: -0.06; 95% CI: -0.15, -0.001; p = .036). CONCLUSION: Improved processing speed may be a mechanism by which exercise reduces subsequent moderate injurious falls in older adults who fell previously. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov Protocol Registration System:NCT01029171: https://clinicaltrials.gov/ct2/show/NCT01029171NCT00323596: https://clinicaltrials.gov/ct2/show/NCT00323596.

A Case-Control Study Investigating Simulated Driving Errors in Ischemic Stroke and Subarachnoid Hemorrhage.

BACKGROUND: Stroke can affect a variety of cognitive, perceptual, and motor abilities that are important for safe driving. Results of studies assessing post-stroke driving ability are quite variable in the areas and degree of driving impairment among patients. This highlights the need to consider clinical characteristics, including stroke subtype, when assessing driving performance. METHODS: We compared the simulated driving performance of 30 chronic stroke patients (>3 months), including 15 patients with ischemic stroke (IS) and 15 patients with subarachnoid hemorrhage (SAH), and 20 age-matched controls. A preliminary analysis was performed, subdividing IS patients into right (n = 8) and left (n = 6) hemispheric lesions and SAH patients into middle cerebral artery (MCA, n = 5) and anterior communicating artery (n = 6) territory. A secondary analysis was conducted to investigate the cognitive correlates of driving. RESULTS: Nine patients (30%) exhibited impaired simulated driving performance, including four patients with IS (26.7%) and five patients with SAH (33.3%). Both patients with IS (2.3 vs. 0.3, U = 76, p < 0.05) and SAH (1.5 vs. 0.3, U = 45, p < 0.001) exhibited difficulty with lane maintenance (% distance out of lane) compared to controls. In addition, patients with IS exhibited difficulty with speed maintenance (% distance over speed limit; 8.9 vs. 4.1, U = 81, p < 0.05), whereas SAH patients exhibited difficulty with turning performance (total turning errors; 5.4 vs. 1.6, U = 39.5, p < 0.001). The Trail Making Test (TMT) and Useful Field of View test were significantly associated with lane maintenance among patients with IS (rs > 0.6, p < 0.05). No cognitive tests showed utility among patients with SAH. CONCLUSION: Both IS and SAH exhibited difficulty with lane maintenance. Patients with IS additionally exhibited difficulty with speed maintenance, whereas SAH patients exhibited difficulty with turning performance. Current results support the importance of differentiating between stroke subtypes and considering other important clinical characteristics (e.g., side of lesion, vascular territory) when assessing driving performance and reinforce the importance of physicians discussing driving safety with patients after stroke.

Investigating Simulated Driving Errors in Amnestic Single- and Multiple-Domain Mild Cognitive Impairment.

The areas of driving impairment characteristic of mild cognitive impairment (MCI) remain unclear. This study compared the simulated driving performance of 24 individuals with MCI, including amnestic single-domain (sd-MCI, n = 11) and amnestic multiple-domain MCI (md-MCI, n = 13), and 20 age-matched controls. Individuals with MCI committed over twice as many driving errors (20.0 versus 9.9), demonstrated difficulty with lane maintenance, and committed more errors during left turns with traffic compared to healthy controls. Specifically, individuals with md-MCI demonstrated greater driving difficulty compared to healthy controls, relative to those with sd-MCI. Differentiating between different subtypes of MCI may be important when evaluating driving safety.

Event-related changes of the prefrontal cortex oxygen delivery and metabolism during driving measured by hyperspectral fNIRS.

Recent technological advancements in optical spectroscopy allow for the construction of hyperspectral (broadband) portable tissue oximeters. In a series of our recent papers we have shown that hyperspectral NIRS (hNIRS) has similar or better capabilities in the absolute tissue oximetry as frequency-domain NIRS, and that hNIRS is also very efficient in measuring temporal changes in tissue hemoglobin concentration and oxygenation. In this paper, we extend the application of hNIRS to the measurement of event-related hemodynamic and metabolic functional cerebral responses during simulated driving. In order to check if hNIRS can detect event-related changes in the brain, we measured the concentration changes of oxygenated (HbO2) and deoxygenated (HHb) hemoglobin and of the oxidized state of cytochrome c oxidase, on the right and left prefrontal cortices (PFC) simultaneously during simulated driving on sixteen healthy right-handed participants (aged between 22-32). We used our in-house hNIRS system based on a portable spectrometer with cooled CCD detector and a driving simulator with a fully functional steering wheel and foot pedals. Each participant performed different driving tasks and participants were distracted during some driving conditions by asking general knowledge true/false questions. Our findings suggest that more complex driving tasks (non-distracted) deactivate PFC while distractions during driving significantly activate PFC, which is in agreement with previous fMRI results. Also, we found the changes in the redox state of the cytochrome C oxidase to be very consistent with those in the concentrations of HbO2 and HHb. Overall our findings suggest that in addition to the suitability of absolute tissue oximetry, hyperspectral NIRS may also offer advantages in functional brain imaging. In particular, it can be used to measure the metabolic functional brain activity during actual driving.

Unruptured intracranial aneurysm treatment effects on cognitive function: a meta-analysis.

OBJECTIVE: The treatment of an unruptured intracranial aneurysm (UIA) is not free of morbidity and mortality, and the decision is made by weighing the risks of treatment complications against the risk of aneurysm rupture. This meta-analysis quantitatively analyzed the literature on the effects of UIA treatment on cognition. METHODS: MEDLINE, Embase, and PsycInfo were systematically searched for studies that reported on the cognitive status of UIA patients before and after aneurysm treatment. The search was restricted to prospective cohort and case-control studies published between January 1, 1998, and January 1, 2013. The analyses focused on the effect of treatment on general cognitive functioning, with an emphasis on 4 specific cognitive domains: executive functions, verbal and visual memory, and visuospatial functions. RESULTS: Eight studies, with a total of 281 patients, were included in the meta-analysis. Treatment did not affect general cognitive functioning (effect size [ES] -0.22 [95% CI -0.78 to 0.34]). Executive functions and verbal memory domains trended toward posttreatment impairment (ES -0.46 [95% CI -0.93 to 0.01] and ES -0.31 [95% CI -1.24 to 0.61]), and performance of visual memory tasks trended toward posttreatment improvement (ES 1.48 [95% CI -0.36 to 3.31]). Lastly, treatment did not significantly affect visuospatial functions (ES -0.08 [95% CI -0.30 to 0.45]). CONCLUSIONS: The treatment of an UIA does not seem to affect long-term cognitive function. However, definitive conclusions were not possible due to the paucity of studies addressing this issue.

Is it safe to drive after acute mild stroke? A preliminary report.

BACKGROUND: Most guidelines recommend that patients should refrain from driving for at least one month after stroke. Despite these guidelines, and the fact that patients post-stroke may be at an increased risk for driving impairment, many patients report resuming driving within the acute phase of injury. The aim of this study was to investigate the driving performance of patients with acute mild stroke. METHODS: The current study compared the driving simulator performance of ten patients with acute mild ischemic stroke (>48 h and <7 days) to that of ten healthy, age- and education-matched controls. RESULTS: During the City Driving and Bus Following Scenarios, patients on average committed over twice as many errors (e.g., collisions, center line crossings, speed exceedances) as controls (12.4 vs. 6.0, t(18)=2.77, p<0.01; and 8.2 vs. 2.1, t(17)=2.55, p<0.05; respectively). Although there was no difference between patients and controls in the number of errors committed during simple right and left turns, patients committed significantly more errors than controls during left turns with traffic (0.49 vs. 0.26, U=26.5, p<0.05). CONCLUSION: Results suggest that patients with acute mild ischemic stroke may be able to maintain driving performance during basic tasks (e.g., straight driving, right turns) and that deficits may become apparent during more complex tasks (e.g., left turns with traffic, bus following). The results highlight the importance of healthcare professionals providing driving advice to their patients post-stroke, particularly in the acute phase of injury.