Beyond Hypertension: Examining Variable Blood Pressure's Role in Cognition and Brain Structure.

Importance: Hypertension is a known risk factor for cognitive decline and structural brain changes in aging and dementia. In addition to high blood pressure (BP), individuals may also experience variable BP, meaning that their BP fluctuates between normal and high. It is currently unclear what the effects of variable BP are on cognition and brain structure. Objective: To investigate the influence of BP on cognition and brain structure in older adults. Design Setting and Participants: This longitudinal cohort study included data from the Rush Alzheimer's Disease Center Research Resource Sharing Hub (RUSH) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants from the two studies were included if they had BP measurements and either cognitive scores or MRI scans from at least one visit. Main Outcomes and Measures: Longitudinal gray matter, white matter, white matter hyperintensity volumes, postmortem neuropathology information, as well as cognitive test scores. Results: A total of 4606 participants (3429 females, mean age = 76.8) with 32776 follow-ups (mean = 7 years) from RUSH and 2114 participants (1132 females, mean age = 73.3) with 9827 follow-ups (mean = 3 years) from ADNI were included in this study. Participants were divided into one of three groups: 1) normal BP, high BP, or variable BP. Older adults with variable BP exhibited the highest rate of cognitive decline followed by high BP and then normal BP. Increased GM volume loss and WMH burden was also observed in variable BP compared to high and normal BP. With respect to post-mortem neuropathology, both variable and high BP had increased severities compared to normal BP. Importantly, results were consistent across the RUSH and ADNI participants, supporting the generalizability of the findings. Conclusion and Relevance: Limited research has examined the long-term impact of variable BP on cognition and brain structure. These findings show the importance that both high and variable BP have on cognitive decline and structural brain changes. Structural damages caused by variable BP may reduce resilience to future dementia-related pathology and increased risk of dementia. Improved treatment and management of variable BP may help reduce cognitive decline in the older adult population.

The influence of APOE status on rate of cognitive decline.

BACKGROUND: Apolipoprotein (APOE) ɛ4 positivity and subjective cognitive decline (SCD) both increase risk of Alzheimer's disease (AD) development. However, few studies have examined the relationship between SCD and APOE status, especially using longitudinal data. The current study examined whether APOE is associated with the rate of cognitive change in SCD and mild cognitive impairment (MCI). METHODS: A sample of 3494 older adults (1990 normal controls, NC, 775 SCD, and 729 MCI) with a mean follow-up of 9.09 years were included from the Rush Alzheimer's Disease Center Research Sharing Hub. Linear mixed effects models examined the relationship between APOE status and cognitive change in older adults with SCD normal controls, and people with MCI. RESULTS: The presence of at least one ɛ2 allele in SCD and MCI results in cognitive change rates similar to a NC with the ɛ3ɛ3 genotype. Older adult SCD-ɛ4 individuals exhibited increased rate of cognitive decline compared to all groups, including NC-ɛ4 and MCI-ɛ4. CONCLUSION: People with SCD with at least one ɛ4 allele experience increased rates of cognitive decline compared to cognitively healthy older adults and people with MCI. These findings have important implications for treatments and interventions and can improve future research and clinical trials by targeting people in the preclinical AD phase (i.e., SCD) who also possess at least one APOE ɛ4 allele.

Structures of the Hepaci-, Pegi-, and Pestiviruses envelope proteins suggest a novel membrane fusion mechanism.

Enveloped viruses encode specialised glycoproteins that mediate fusion of viral and host membranes. Discovery and understanding of the molecular mechanisms of fusion have been achieved through structural analyses of glycoproteins from many different viruses, and yet the fusion mechanisms of some viral genera remain unknown. We have employed systematic genome annotation and AlphaFold modelling to predict the structures of the E1E2 glycoproteins from 60 viral species in the Hepacivirus, Pegivirus, and Pestivirus genera. While the predicted structure of E2 varied widely, E1 exhibited a very consistent fold across genera, despite little or no similarity at the sequence level. Critically, the structure of E1 is unlike any other known viral glycoprotein. This suggests that the Hepaci-, Pegi-, and Pestiviruses may possess a common and novel membrane fusion mechanism. Comparison of E1E2 models from various species reveals recurrent features that are likely to be mechanistically important and sheds light on the evolution of membrane fusion in these viral genera. These findings provide new fundamental understanding of viral membrane fusion and are relevant to structure-guided vaccinology.

Subjective Cognitive Decline Is Associated With Lower Baseline Cognition and Increased Rate of Cognitive Decline.

OBJECTIVES: Subjective cognitive decline (SCD) is a known risk factor for Alzheimer's disease. However, little research has examined whether healthy older adults with SCD (SCD+) exhibit lower cognition and increased rates of cognitive decline compared to those without SCD (SCD-). The goal of this study was to examine if cognitive change over a 15-year period differs between SCD+ and SCD-. METHOD: 3,019 cognitively normal older adults (831 SCD+) from 3 Rush Alzheimer's Disease Center cohort studies were followed annually for up to a maximum of 15 years. Due to attrition, the average follow-up time was 5.7 years. Cognition was measured using z-scores of global cognition, episodic memory, semantic memory, perceptual speed, visuospatial ability, and working memory. Linear mixed-effects models investigated whether SCD was associated with cognitive change. RESULTS: Both baseline cognition and cognitive change over time differed between SCD+ and SCD-. People with SCD+ exhibited lower baseline scores and a steeper decline in global cognition, episodic memory, semantic memory, and perceptual speed. People with SCD+ did not differ from SCD- in baseline visuospatial ability or working memory but exhibited increased change over time in those two domains compared to SCD-. DISCUSSION: The observed results reveal that older adults with SCD+ have lower baseline cognition and steeper declines in cognition over time compared to SCD-. Older adults with SCD may be aware of subtle cognitive declines that occur over time in global cognition, episodic memory, semantic memory, perceptual speed, visuospatial ability, and working memory compared to those without SCD.

Validating the accuracy of a novel virtual reality platform for determining implant orientation in simulated primary total hip replacement.

Introduction: Accurate acetabular cup and femoral stem component orientation are critical for optimising patient outcomes, reducing complications and increasing component longevity following total hip replacement (THR). This study aimed to determine the accuracy of a novel virtual reality (VR) platform in assessing component orientation in a simulated THR model. Methods: The VR platform (HTC Vive Pro® system hardware) was compared against the validated Vicon® optical motion capture (MoCap) system. An acetabular cup and femoral stem were manually implanted across a range of orientations into pelvic and femur sawbones, respectively. Simultaneous readings of the acetabular cup operative anteversion (OA) and inclination (OI) and femoral stem alignment (FSA) and neck anteversion (FNA) were obtained from the VR and MoCap systems. Statistical analysis was performed using Pearson product-moment correlation coefficient (PPMCC) (Pearson's r) and linear regression (R2). Results: A total of 55 readings were obtained for the acetabular cup and 68 for the femoral stem model. The mean average differences in OA, OI, FSA and FNA between the systems were 3.44°, -0.01°, 0.01° and -0.04°, respectively. Strong positive correlations were demonstrated between both systems in OA, OI, FSA and FNA, with Pearson's r = 0.92, 0.94, 0.99 and 0.99, and adjusted R2 = 0.82, 0.9, 0.98 and 0.98, respectively. Conclusion: The novel VR platform is highly accurate and reliable in determining both acetabular cup and femoral stem component orientations in simulated THR models. This adaptable and cost-effective digital tracking platform may be modified for use in a range of simulated surgical training and educational purposes, particularly in orthopaedic surgery.

Subjective cognitive decline is a better marker for future cognitive decline in females than in males.

BACKGROUND: The identification of biomarkers for early detection of Alzheimer's disease (AD) is critical to the development of therapies and interventions targeted at symptom management and tracking the pathophysiology of disease. The endorsement of subjective cognitive decline (SCD) has emerged as a potential indicator of early change in cognitive status that may be predictive of future impairment at a time when measurable declines in neuropsychological performance cannot be detected. While there are numerous findings revealing sex differences in the prevalence of AD, there is a paucity of research examining sex differences in SCD. Therefore, the goal of this project was to determine if the relationship between the endorsement of SCD and future cognitive changes differ as a function of biological sex. METHODS: A sample of 3019 male and female healthy older adults (2188 without SCD, 831 with SCD), with a mean follow-up time of 5.7 years, were included from the Rush Alzheimer's Disease Center Research Sharing Hub. Linear regressions were performed to determine group differences in baseline cognitive scores, while linear mixed-effects models were completed to determine group differences in the rate of cognitive change over time. RESULTS: Individuals endorsing SCD had significantly lower baseline cognitive scores and increased rates of decline in all cognitive domains compared to those without SCD. Males exhibited significantly lower scores in baseline performance in global cognition, episodic memory, and perceptual speed regardless of SCD classification. Females with SCD were found to decline at significantly faster rates than both males with SCD and males and females without SCD in all cognitive domains over a maximum 15-year follow-up period. CONCLUSIONS: SCD is related to lower baseline cognitive performance and faster cognitive decline compared to those who do not endorse SCD. Females with SCD have the fastest rate of decline suggesting that SCD may be more predictive of future decline in females than in males. Targeted assessments of SCD may allow for the identification of individuals for inclusion in intervention trials, and other research studies, aiming to attenuate casual disease processes, which may ultimately aid in the mitigation of sex disparities in AD.

The Impact of a Cyberattack at a Radiation Oncology Department: Immediate Response and Future Preparedness.

Cyberattacks are increasing year after year and many organizations, including hospitals, are becoming targets. Radiation oncology is especially vulnerable because of the reliance on computer and network capabilities to transfer relevant patient information for safe and effective patient treatment. In early 2019, our institution was hit by a ransomware attack that brought down our oncology information system (OIS). Although we were not fully prepared for such an attack, a total of 69 treatment fractions occurred without our OIS thanks to the quick development of a contingency plan and the ability to restore the patients' records. The OIS was recovered by the manufacturer 4 days after the attack. We also have developed a contingency plan and outline important considerations for institutions trying to prepare for unexpected downtime such as a cyberattack.

Addressing health disparities in hispanic communities through an innovative team-based medical spanish program at the medical school level - a single-institution study.

BACKGROUND: There are insufficient Spanish-speaking physicians to effectively serve a large and rapidly growing Spanish-speaking patient population. METHODS: A team-based hybrid medical Spanish program was designed and implemented at a single medical school in Southern California. This pilot program consisted of a weekly in-person portion where students reviewed Spanish vocabulary and grammar and practiced clinical encounters in teams through active role play. Students supplemented in-class learning with online coursework. Program success was measured through physician-evaluated clinical encounters with Spanish-speaking standardized patients, a 100-question multiple-choice exam, and pre- and post-program surveys. RESULTS: 97% of students in the program (n = 32) received a passing grade at program completion. Student surveys demonstrated enthusiasm and engagement in weekly sessions (95% overall attendance, 97% reported feeling either excited or ready to learn prior to class). In a post-program survey, 100% of students felt better suited and increased desire to treat Hispanic patients. Additionally, all students indicated an interest in the continued use of Spanish in both their schooling and future practice. In a follow-up survey after three months of clinical experience in their 3rd year of medical school, 100% of students reported that medical Spanish is "very beneficial" in patient care and that students with medical Spanish proficiency have advantages over non-speaking students when it comes to patient care opportunities. 100% felt that time spent learning medical Spanish during pre-clinical years was time well spent and that the medical Spanish program enhanced their care of Spanish-speaking students. CONCLUSIONS: The results of the pilot program show a significant increase in the ability of students to engage in clinical interaction in Spanish. The results of our study demonstrate a significant increase in the knowledge, clinical skills, and self-reported confidence of students to treat Hispanic patients. Furthermore, all students not only felt better equipped and more confident to treat Hispanic patients, but they also had an increased desire to do so moving forward in their careers. We conclude that an effective medical Spanish program can be executed simultaneously with a pre-clinical medical school curriculum.

The Mediterranean dietary pattern for optimising health and performance in competitive athletes: a narrative review.

Nutrition plays a key role in training for, and competing in, competitive sport, and is essential for reducing risk of injury and illness, recovering and adapting between bouts of activity, and enhancing performance. Consumption of a Mediterranean diet (MedDiet) has been demonstrated to reduce risk of various non-communicable diseases and increase longevity. Following the key principles of a MedDiet could also represent a useful framework for good nutrition in competitive athletes under most circumstances, with potential benefits for health and performance parameters. In this review, we discuss the potential effects of a MedDiet, or individual foods and compounds readily available in this dietary pattern, on oxidative stress and inflammation, injury and illness risk, vascular and cognitive function, and exercise performance in competitive athletes. We also highlight potential modifications which could be made to the MedDiet (whilst otherwise adhering to the key principles of this dietary pattern) in accordance with contemporary sports nutrition practices, to maximise health and performance effects. In addition, we discuss potential directions for future research.

Evaluating the Fitness-to-Drive Using Evoked Visual Responses in Alzheimer's Disease.

Alzheimer's Disease (AD) is the sixth leading cause of death in the US. AD causes significant disability due to the devastating impact on the patients' day-to-day living activities and their loss of independence. One such day-to-day activity is driving, a complex task that requires attention, concentration, the ability to follow particular steps, react to stimuli promptly, and the ability to perceive and interpret visual-spatial information, all of which can be impaired in AD. Therefore, to ensure the safety of AD patients and other drivers, it is important to develop accurate and low-cost diagnostic tools to assess patients' fitness-to-drive. In this study, we develop machine learning (ML) models to predict fitness-to-drive using the electroencephalogram (EEG) technique of event-related potential (ERP). Specifically, we develop random forest (RF) models using EEG signals in early-stage AD patients and age-matched controls and conduct numerical experiments to predict fitness-to-drive and other driving performance metrics, collected from driving simulator data. Our results show that RF models predict patients' fitness-to-drive with AUC=0.83 and provide accurate measures of other driving performance metrics. Therefore, ML and ERP offer a valuable approach to assess driving safety for patients with early AD symptoms in the laboratory setting.

Removing independent noise in systems neuroscience data using DeepInterpolation.

Progress in many scientific disciplines is hindered by the presence of independent noise. Technologies for measuring neural activity (calcium imaging, extracellular electrophysiology and functional magnetic resonance imaging (fMRI)) operate in domains in which independent noise (shot noise and/or thermal noise) can overwhelm physiological signals. Here, we introduce DeepInterpolation, a general-purpose denoising algorithm that trains a spatiotemporal nonlinear interpolation model using only raw noisy samples. Applying DeepInterpolation to two-photon calcium imaging data yielded up to six times more neuronal segments than those computed from raw data with a 15-fold increase in the single-pixel signal-to-noise ratio (SNR), uncovering single-trial network dynamics that were previously obscured by noise. Extracellular electrophysiology recordings processed with DeepInterpolation yielded 25% more high-quality spiking units than those computed from raw data, while DeepInterpolation produced a 1.6-fold increase in the SNR of individual voxels in fMRI datasets. Denoising was attained without sacrificing spatial or temporal resolution and without access to ground truth training data. We anticipate that DeepInterpolation will provide similar benefits in other domains in which independent noise contaminates spatiotemporally structured datasets.

Granulovirus PK-1 kinase activity relies on a side-to-side dimerization mode centered on the regulatory αC helix.

The life cycle of Baculoviridae family insect viruses depends on the viral protein kinase, PK-1, to phosphorylate the regulatory protein, p6.9, to induce baculoviral genome release. Here, we report the crystal structure of Cydia pomenella granulovirus PK-1, which, owing to its likely ancestral origin among host cell AGC kinases, exhibits a eukaryotic protein kinase fold. PK-1 occurs as a rigid dimer, where an antiparallel arrangement of the αC helices at the dimer core stabilizes PK-1 in a closed, active conformation. Dimerization is facilitated by C-lobe:C-lobe and N-lobe:N-lobe interactions between protomers, including the domain-swapping of an N-terminal helix that crowns a contiguous ß-sheet formed by the two N-lobes. PK-1 retains a dimeric conformation in solution, which is crucial for catalytic activity. Our studies raise the prospect that parallel, side-to-side dimeric arrangements that lock kinase domains in a catalytically-active conformation could function more broadly as a regulatory mechanism among eukaryotic protein kinases.

Relationship between urinary nitrate concentrations and cognitive function in older adults: findings from the NHANES survey.

This study evaluated the association of urinary nitrate concentrations with cognition in older subjects enrolled in the NHANES study. We also explored whether associations between urinary nitrate and cognition were modified by cardiovascular risk, vitamin D status and vitamin C intake. Two NHANES cycles were merged (2011-2012 and 2013-2014) and a total of 1,015 adults aged 60-80 (69.4 ± 0.3) years were included. Cognition was assessed using the Word List Learning, Word List Recall, Animal Fluency and the Digit Symbol Substitution tests. Urinary nitrate was analysed using electrospray tandem mass spectrometry. Urinary nitrate concentrations were not associated with cognitive performance on any of the cognitive tests. Associations were also not significant in subjects at greater risk for cognitive impairment (i.e. high cardiovascular risk and non-optimal vitamin D status). Longitudinal analyses are needed to explore the associations of urinary nitrate concentrations with dietary nitrate intake and cognitive function.

Predicting Alzheimer's Disease Using Driving Simulator Data.

Early detection of Alzheimer's Disease (AD) is critical in creating better outcomes for patients. Performance in complex tasks such as vehicular driving may be a sensitive tool for early detection of AD and serve as a good indicator of functional status. In this study, we investigate the classification of AD patients and controls using driving simulator data. Our results show that machine learning algorithms, especially random forest classifier, can accurately discriminate AD patients and controls (AUC = 0.96, Sensitivity = 87%, and Specificity = 93%). The model-identified most important features include Pothole Avoidance, Road Signs Recalled, Inattention Measurements, Reaction Time, and Detection Times, among others, all of which closely align with previous studies about cognitive functions that are affected by AD.

The roles of repetitive negative thinking and perfectionism in explaining the relationship between sleep onset difficulties and depressed mood in adolescents.

OBJECTIVE: The present study investigated the relationship between difficulty initiating sleep and depressed mood and whether it is mediated by repetitive negative thinking. A moderating role of perfectionism was also examined. METHODS: We surveyed 393 adolescents aged 14 to 20 years (M = 17.32, SD = 1.90) via an online questionnaire that assessed difficulty initiating sleep, repetitive negative thinking, perfectionism, and depressed mood. RESULTS: Results indicated that repetitive negative thinking fully mediated the relationship between difficulty initiating sleep and depressed mood. In addition, this relationship was moderated by perfectionism, specifically, the relationship between repetitive negative thinking and depressed mood was stronger among more perfectionistic adolescents. CONCLUSIONS: These findings highlight that repetitive negative thinking is significantly associated with both difficulty initiating sleep and depressed mood, supporting the conceptualization of repetitive negative thinking as a transdiagnostic process. Further, individual differences in perfectionism may amplify the relationship between repetitive negative thinking and mood. The role of repetitive negative thinking and perfectionism in explaining the link between sleep onset problems and depressed mood has important clinical implications through providing possible treatment targets.

The relationship between sleep and autonomic health.

Objective: To examine the relationship between sleep and resting autonomic nervous system (ANS) functioning in college students. Participants: Participants were 141 undergraduate students (52 males) recruited from a large southeastern university during September-October 2017. Methods: Participants completed self-report inventories (demographic and sleep characteristics). Resting state skin conductance (SC) and heart rate variability (HRV) were measured in a laboratory setting for ANS functioning. Results: SC was positively associated with sleep quality (p = 0.027), sleep latency (p = 0.040), and use of sleep medication (p < 0.001). Analyses yielded a negative association between the standard deviation of the normal-normal interval of heart beats (SDNN) and the self-reported amount of time to fall asleep each night (p = 0.041). Sleep efficiency was negatively correlated with low frequency HRV (p = 0.002). Conclusions: Sleep components are associated with resting ANS activity, and targeted interventions focused on improved ANS functioning may benefit sleep quality in college students.