Clinical Reasoning: A 38-Year-Old Woman Presenting With Acute Hyperkinetic Movements of Her Right Arm.

We present a case report of a 38-year-old woman who presented to the hospital with acute onset high amplitude, non-rhythmic, hyperkinetic movements of the right upper extremity, abnormal sensation of the right upper extremity from the elbow to the hand, and the inability to recognize her hand without visual input. This case discusses the differential diagnoses of acute hyperkinetic movement disorders and concurrent alien-limb in a patient presenting within the time window for vascular intervention. Readers are led through the reasoning behind acute interventional decision-making in a patient with a rare presentation. Workup reveals the eventual diagnosis.

Cardioembolic stroke in the setting of diffuse caseous calcification of the anterolateral papillary muscle.

A woman in her 70s was admitted for acute, painless vision loss in the left eye. Examination showed cherry red spot in the macula and plaque in the nasal vessels, consistent with central retinal artery occlusion. MRI orbits revealed multifocal subclinical acute infarcts in the right middle cerebral artery (MCA) territory and bilateral cerebella. Transthoracic echocardiogram showed calcification of the anterolateral papillary muscle. Further characterisation with cardiac MRI elucidated caseous 'toothpaste-like' calcification of the muscle complex. Stroke workup was otherwise unremarkable. The patient underwent hyperbaric treatment with mild improvement. Anticoagulation and surgical intervention were deferred due to known risks and unknown benefit for calcific emboli. The patient was continued on her home dual anti-platelet therapy (DAPT) and discharged with a loop monitor. Caseous calcification of the papillary muscle (CCPM) may be a risk factor for cardioembolic stroke. Further discussions on medical and surgical guidelines for CCPM would be beneficial for stroke prevention.

Libkrylov: A modular open-source software library for extremely large on-the-fly matrix computations.

We present the design and implementation of libkrylov, an open-source library for solving matrix-free eigenvalue, linear, and shifted linear equations using Krylov subspace methods. The primary objectives of libkrylov are flexible API design and modular structure, which enables integration with specialized matrix-vector evaluation "engines." Libkrylov features pluggable preconditioning, orthonormalization, and tunable convergence control. Diagonal (conjugate gradient, CG), Davidson, and Jacobi-Davidson preconditioners are available, along with orthonormal and nonorthonormal (nKs) schemes. All functionality of libkrylov is exposed via Fortran and C application programming interfaces (APIs). We illustrate the performance of libkrylov for eigenvalue calculations arising in time-dependent density functional theory (TDDFT) in the Tamm-Dancoff approximation (TDA) and discuss the convergence behavior as a function of preconditioning and orthonormalization methods.

Beer, wine, and spirits differentially influence body composition in older white adults-a United Kingdom Biobank study.

BACKGROUND: Aging is characterized by body composition alterations, including increased visceral adiposity accumulation and bone loss. Alcohol consumption may partially drive these alterations, but findings are mixed. This study primarily aimed to investigate whether different alcohol types (beer/cider, red wine, white wine/Champagne, spirits) differentially associated with body composition. METHODS: The longitudinal UK Biobank study leveraged 1869 White participants (40-80 years; 59% male). Participants self-reported demographic, alcohol/dietary consumption, and lifestyle factors using a touchscreen questionnaire. Anthropometrics and serum for proteomics were collected. Body composition was obtained via dual-energy X-ray absorptiometry. Structural equation modeling was used to probe direct/indirect associations between alcohol types, cardiometabolic biomarkers, and body composition. RESULTS: Greater beer/spirit consumptions were associated with greater visceral adiposity (ß = 0.069, p < 0.001 and ß = 0.014, p < 0.001, respectively), which was driven by dyslipidemia and insulin resistance. In contrast, drinking more red wine was associated with less visceral adipose mass (ß = -0.023, p < 0.001), which was driven by reduced inflammation and elevated high-density lipoproteins. White wine consumption predicted greater bone density (ß = 0.051, p < 0.005). DISCUSSION: Beer/spirits may partially contribute to the "empty calorie" hypothesis related to adipogenesis, while red wine may help protect against adipogenesis due to anti-inflammatory/eulipidemic effects. Furthermore, white wine may benefit bone health in older White adults.1.

Using machine learning to predict COVID-19 infection and severity risk among 4510 aged adults: a UK Biobank cohort study.

Many risk factors have emerged for novel 2019 coronavirus disease (COVID-19). It is relatively unknown how these factors collectively predict COVID-19 infection risk, as well as risk for a severe infection (i.e., hospitalization). Among aged adults (69.3 ± 8.6 years) in UK Biobank, COVID-19 data was downloaded for 4510 participants with 7539 test cases. We downloaded baseline data from 10 to 14 years ago, including demographics, biochemistry, body mass, and other factors, as well as antibody titers for 20 common to rare infectious diseases in a subset of 80 participants with 124 test cases. Permutation-based linear discriminant analysis was used to predict COVID-19 risk and hospitalization risk. Probability and threshold metrics included receiver operating characteristic curves to derive area under the curve (AUC), specificity, sensitivity, and quadratic mean. Model predictions using the full cohort were marginal. The "best-fit" model for predicting COVID-19 risk was found in the subset of participants with antibody titers, which achieved excellent discrimination (AUC 0.969, 95% CI 0.934-1.000). Factors included age, immune markers, lipids, and serology titers to common pathogens like human cytomegalovirus. The hospitalization "best-fit" model was more modest (AUC 0.803, 95% CI 0.663-0.943) and included only serology titers, again in the subset group. Accurate risk profiles can be created using standard self-report and biomedical data collected in public health and medical settings. It is also worthwhile to further investigate if prior host immunity predicts current host immunity to COVID-19.

APOE, TOMM40, and sex interactions on neural network connectivity.

The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs2075650 ('650) G versus A carriage is consistently related to neural and cognitive outcomes, but it is unclear if and how it interacts with APOE. We examined 21 orthogonal neural networks among 8,222 middle-aged to aged participants in the UK Biobank cohort. ANOVA and multiple linear regression tested main effects and interactions with APOE and TOMM40 '650 genotypes, and if age and sex acted as moderators. APOE ε4 was associated with less strength in multiple networks, while '650 G versus A carriage was related to more language comprehension network strength. In APOE ε4 carriers, '650 G-carriage led to less network strength with increasing age, while in non-G-carriers this was only seen in women but not men. TOMM40 may shift what happens to network activity in aging APOE ε4 carriers depending on sex.

Inflammation, negative affect, and amyloid burden in Alzheimer's disease: Insights from the kynurenine pathway.

BACKGROUND: Depressive symptoms in Alzheimer's disease (AD) predict worse cognitive and functional outcomes. Both AD and major depression inflammatory processes are characterized by shunted tryptophan metabolism away from serotonin (5-HT) and toward the neuroinflammatory kynurenine (Kyn) pathway. The present study assessed associations between Kyn and behavioral, neuroanatomical, neuropathological, and physiological outcomes common to both AD and negative affect across the AD continuum. METHODS: In 58 cognitively normal, 396 mild cognitive impairment, and 112 AD participants from the Alzheimer's Disease Neuroimaging Initiative-1 (ADNI1) cohort, serum markers of 5-HT, tryptophan, and Kyn were measured and their relationships investigated with immunologic markers, affect and functional outcomes, CSF markers of beta-amyloid (Aß) and tau, and regional gray matter. RESULTS: A higher Kyn/Tryptophan ratio was linked to many inflammatory markers, as well as lower functional independence and memory scores. A higher Kyn/5-HT ratio showed similar associations, but also strong relationships with negative affect and neuropsychiatric disturbance, executive dysfunction, and global cognitive decline. Further, gray matter atrophy was seen in hippocampus, anterior cingulate, and prefrontal cortices, as well as greater amyloid and total tau deposition. Finally, using moderated-mediation, several pro-inflammatory factors partially mediated Kyn/5-HT and negative affect scores in participants with subclinical Aß (i.e., Aß-), whereas such associations were fully mediated by Complement 3 in Aß+ participants. CONCLUSION: These findings suggest that inflammatory signaling cascades may occur during AD, which is associated with increased Kyn metabolism that influences the pathogenesis of negative affect. Aß and the complement system may be critical contributing factors in this process.

Using machine learning to predict COVID-19 infection and severity risk among 4,510 aged adults: a UK Biobank cohort study.

BACKGROUND: Many risk factors have emerged for novel 2019 coronavirus disease (COVID-19). It is relatively unknown how these factors collectively predict COVID-19 infection risk, as well as risk for a severe infection (i.e., hospitalization). METHODS: Among aged adults (69.3 ± 8.6 years) in UK Biobank, COVID-19 data was downloaded for 4,510 participants with 7,539 test cases. We downloaded baseline data from 10-14 years ago, including demographics, biochemistry, body mass, and other factors, as well as antibody titers for 20 common to rare infectious diseases. Permutation-based linear discriminant analysis was used to predict COVID-19 risk and hospitalization risk. Probability and threshold metrics included receiver operating characteristic curves to derive area under the curve (AUC), specificity, sensitivity, and quadratic mean. RESULTS: The "best-fit" model for predicting COVID-19 risk achieved excellent discrimination (AUC=0.969, 95% CI=0.934-1.000). Factors included age, immune markers, lipids, and serology titers to common pathogens like human cytomegalovirus. The hospitalization "best-fit" model was more modest (AUC=0.803, 95% CI=0.663-0.943) and included only serology titers. CONCLUSIONS: Accurate risk profiles can be created using standard self-report and biomedical data collected in public health and medical settings. It is also worthwhile to further investigate if prior host immunity predicts current host immunity to COVID-19.

Genetic Factors of Alzheimer's Disease Modulate How Diet is Associated with Long-Term Cognitive Trajectories: A UK Biobank Study.

BACKGROUND: Fluid intelligence (FI) involves abstract problem-solving without prior knowledge. Greater age-related FI decline increases Alzheimer's disease (AD) risk, and recent studies suggest that certain dietary regimens may influence rates of decline. However, it is uncertain how long-term food consumption affects FI among adults with or without familial history of AD (FH) or APOE4 (ɛ4). OBJECTIVE: Observe how the total diet is associated with long-term cognition among mid- to late-life populations at-risk and not-at-risk for AD. METHODS: Among 1,787 mid-to-late-aged adult UK Biobank participants, 10-year FI trajectories were modeled and regressed onto the total diet based on self-reported intake of 49 whole foods from a Food Frequency Questionnaire (FFQ). RESULTS: Daily cheese intake strongly predicted better FIT scores over time (FH-: ß= 0.207, p < 0.001; ɛ4-: ß= 0.073, p = 0.008; ɛ4+: ß= 0.162, p = 0.001). Alcohol of any type daily also appeared beneficial (ɛ4+: ß= 0.101, p = 0.022) and red wine was sometimes additionally protective (FH+: ß= 0.100, p = 0.014; ɛ4-: ß= 0.59, p = 0.039). Consuming lamb weekly was associated with improved outcomes (FH-: ß= 0.066, p = 0.008; ɛ4+: ß= 0.097, p = 0.044). Among at risk groups, added salt correlated with decreased performance (FH+: ß= -0.114, p = 0.004; ɛ4+: ß= -0.121, p = 0.009). CONCLUSION: Modifying meal plans may help minimize cognitive decline. We observed that added salt may put at-risk individuals at greater risk, but did not observe similar interactions among FH- and AD- individuals. Observations further suggest in risk status-dependent manners that adding cheese and red wine to the diet daily, and lamb on a weekly basis, may also improve long-term cognitive outcomes.

Factors affecting time between symptom onset and emergency department arrival in stroke patients.

BACKGROUND AND PURPOSE: Delays in seeking care compromise diagnosis, treatment options, and outcomes in ischemic strokes. This study identified factors associated with time between stroke symptom onset and emergency department (ED) arrival at a private nonprofit medical center serving a large rural catchment area in central Texas, with the goal of identifying symptomatic, demographic, and historical factors that might influence seeking care. METHODS: Demographic and clinical data from a large tertiary care center's Get With The Guidelines (GWTG) database were evaluated in 1874 patients presenting to the ED with a diagnosis of transient ischemic attack (TIA), intracranial hemorrhage, subarachnoid hemorrhage, or ischemic stroke. The dependent variable was time between discovery of stroke symptoms and presentation at the hospital (time-to-ED). Factors entered into regression models predicting time-to-ED within 4 h or categorical time-to-ED. RESULTS: The average time from symptom onset to presentation was 15.0 h (sd = 23.2), with 43.6% of the sample presenting within 4 h of symptom onset. Results suggested that female gender (Odds Ratio [OR] = 0.70; 95% Confidence Interval [CI] 0.23-0.74), drug abuse (OR = 0.41; CI 0.23-0.74), and diabetes were significantly associated with longer time to presentation. CONCLUSIONS: A combination of demographics, stroke severity, timing, and health history contributes to delays in presenting for treatment for ischemic stroke. Stroke education concentrating on symptom recognition may benefit from a special focus on high-risk individuals as highlighted in this study.

CSF glucose tracks regional tau progression based on Alzheimer's disease risk factors.

INTRODUCTION: Glucose hypometabolism and tau formation are key features of Alzheimer's disease (AD). Less is known about the relationship between fasting glucose and regional tau accumulation. METHODS: Cerebrospinal fluid (CSF) glucose was linearly regressed on regional tau (flortaucipir) among 169 Alzheimer's Disease Neuroimaging Initiative (ADNI3) participants. Flortaucipir uptake was examined by Braak stages and regions of interest (ROIs). Interactions were explored between CSF glucose and AD risk factors including regional amyloid beta (Aß), sex, Apolipoprotein E ε4 (APOEε4) status, AD parental family history (AD FH), and cognitive impairment (CI). RESULTS: Interactions found higher CSF glucose tracked less tau in ROIs or Braak stages I/II (women, APOE ε4+, regional Aß), III/IV (AD FH+, regional Aß), and V/VI (AD FH+). CI drove Braak III-VI associations. DISCUSSION: Among women and APOE ε4 carriers, higher CSF glucose tracked less early-stage tau. Higher CSF glucose may reflect compensation against tau spreading in CI, Aß+, or AD FH+.

Walking in the Light: How History of Physical Activity, Sunlight, and Vitamin D Account for Body Fat-A UK Biobank Study.

OBJECTIVE: The high prevalence of vitamin D deficiency and obesity drives the need for successful strategies that elevate vitamin D levels, prevent adipogenesis, and stimulate lipolysis. This study provides a theoretical model to evaluate how physical activity (PA) and sunlight exposure influence serum vitamin D levels and regional adiposity. This study hypothesized a posteriori that sunlight is associated with undifferentiated visceral adiposity by increasing the ratio of brown to white adipose tissue. METHODS: Using 10-year longitudinal data, accelerometry, a sun-exposure questionnaire, and regional adiposity quantified by dual-energy x-ray absorptiometry imaging, a structural-equation mediation model of growth curves was constructed with a data-driven methodology. RESULTS: Sunlight and PA conjointly increased serum vitamin D. Changes in vitamin D levels partially mediated how sunlight and PA impacted adiposity in visceral and subcutaneous regions within a subjective PA model. In an objective PA model, vitamin D was a mediator for subcutaneous regions only. Interestingly, sunlight was associated with less adiposity in subcutaneous regions but greater adiposity in visceral regions. CONCLUSIONS: Sunlight and PA may increase vitamin D levels. For the first time, this study characterizes a positive association between sunlight and visceral adiposity. Further investigation and experimentation are necessary to clarify the physiological role of sunlight exposure on adipose tissue.

Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting.

PURPOSE OF REVIEW: Cervicocephalic arterial dissection (CeAD) is the most commonly identified cause of stroke in young healthy individuals. The management of acute ischemic stroke due to the diagnosed or suspected CeAD is well established and is appropriate for thrombolysis. There is a substantial risk of stroke recurrence in the early post-stroke period. The optimum method of stroke prevention in the subacute period remains debatable. In our review, we focused on the management of recurrent stroke in CeAD, the choice of various antithrombotic agents for stroke risk reduction with regard to specific pathogenetic mechanisms of dissections, and the utility of endovascular therapy. RECENT FINDINGS: Recent studies suggest that various pathogenetic types of CeAD based on radiologic characteristics may be associated with greater risk of thrombogenicity, especially in the early post-stroke period. The use of anticoagulants has been shown to be effective in the eliminating microembolic signals (MES) detected by transcranial Doppler (TCD). The only randomized trial that compared combinations of antiplatelet agents and vitamin K-agonist anticoagulation did not find significant difference in risk of stroke, major bleeding, or mortality. The benefit of dual antiplatelet therapy cannot be excluded. Limited data on the use of direct oral anticoagulant agents (DOAC) is currently available. Endovascular therapy with stenting, while potentially effective, may pose significant risk of complications. Therefore, it needs to be carefully considered on a case-to-case basis. The recurrence of ischemic stroke in patients with CeAD is overall rare. No significant difference in treatment with various antiplatelet and anticoagulant agents has been shown in randomized trials. Only a few studies were based on radiological characteristics of dissections. An ongoing randomized trial is investigating the role of MES and the efficacy of antiplatelet versus anticoagulation agents. The role of DOAC agents has yet to be determined in clinical trials. Stenting in CeAD is an effective revascularization technique and may be considered in selected patients. However, current data is only based on low evidence level findings from small studies, lacking longitudinal outcomes and prognosis.

Aging-related changes in fluid intelligence, muscle and adipose mass, and sex-specific immunologic mediation: A longitudinal UK Biobank study.

BACKGROUND: Obesity in midlife and early late-life is associated with worse normal cognitive aging. Dual-energy X-ray absorptiometry (DEXA) suggests that visceral adipose mass (VAM) plays a predominant role, whereas non-visceral adipose mass (NVAM) and lean muscle mass (LMM) have shown conflicting relationships. It is unknown how longitudinal, cognitive changes in age-sensitive domains like fluid intelligence (FI) correspond to VAM, NVAM, and LMM in women and men. Furthermore, changes over time in blood leukocyte sub-populations may partially or fully account for sex-specific associations. METHODS: Data on 4431 late middle-aged, cognitively unimpaired adults (mean = 64.5 y) was obtained from the UK Biobank prospective cohort across 22 centers. FI scores, blood leukocyte counts, and covariates (age, social class, education) were measured at three 2-year intervals over 6 years. DEXA collection overlapped with these intervals. Sex-stratified growth curves, structural equations, and Preacher-Hayes mediation were used to estimate direct and indirect effects. ß-weights were standardized. RESULTS: More LMM predicted gains in FI scores among women (ß = 0.130, p < .001) and men (ß = 0.089, p < .001). Conversely, more VAM and NVAM independently predicted FI decline equally among sexes (e.g., NVAM: women: ß = -0.082, p < .001; men: ß = -0.076, p < .001). Among women, FI associations were fully mediated by higher eosinophil counts via VAM (λ = 30.8%, p = .028) and lower lymphocyte counts via LMM (λ = 69.2%, p = .021). Among men, FI associations were partially mediated by lower basophils counts via LMM (λ = 4.5%, p = .042) and higher counts via VAM (λ = 50%, p = .037). CONCLUSION: The proportion of LMM and VAM equally influenced male FI changes over 6 years, whereas higher LMM among women appeared to more strongly influence. FI changes. Leukocyte counts strongly mediated VAM- and LMM-related FI changes in a sex-specific manner, but not for NVAM. For clinical translation, exercise studies in older adults may benefit from assessing sex-specific values of DEXA-based tissue mass, FI, and leukocyte sub-populations to gauge potential cognitive benefits of less VAM and more LMM.