A center experience with lung transplantation for COVID-19 ARDS.

COVID-19 can cause irreversible lung damage from acute respiratory distress syndrome (ARDS), chronic respiratory failure associated with post COVID-19 de novo fibrosis or worsening of an underlying fibrotic lung disease. Pregnant women are at increased risk for invasive mechanical ventilation, extracorporeal membrane oxygenation, and death. The Centers for Disease Control and Prevention reported more than 22,000 hospitalizations and 161 deaths for COVID-19 in pregnant women. Between August 2020 and September 2021, five patients underwent bilateral lung transplant (LT) for COVID-19 ARDS at the Henry Ford Hospital in Detroit, Michigan. De-identified demographics data, clinical characteristics, perioperative challenges, explanted lung pathology, and post-transplant outcomes are described. In post-hospitalization follow-up (median survival 273 days), we see improving endurance and excellent lung function. One patient did not survive to hospital discharge and succumbed to complications 5 months after LT. We report the first cases of bilateral LT in two postpartum women.

Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer's Disease.

This pilot study examined the status of the master iron regulatory peptide, hepcidin, and peripheral related iron parameters in Alzheimer's disease (AD) and mild cognitive impairment patients, and evaluated the relationship between iron dyshomeostasis and amyloid-beta (Aß), cognitive assessment tests, neuroimaging and clinical data. Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of hepcidin, ferritin, Aß40, Aß42 using enzyme-linked immunosorbent assay. Serum transferrin levels were determined indirectly as total iron binding capacity, serum iron was measured and the percent saturation of transferrin calculated. The study variables were correlated with the patients' existing cognitive assessment tests, neuroimaging, and clinical data. Hepcidin, and iron-related proteins tended to be higher in AD patients than controls, reaching statistical significance for ferritin, whereas Aß40, Aß42 serum levels tended to be lower. Patients with pure AD had three times higher serum hepcidin levels than controls; gender differences in hepcidin and iron-related proteins were observed. Patient stratification based on clinical dementia rating-sum of boxes revealed significantly higher levels of iron and iron-related proteins in AD patients in the upper 50% as compared to controls, suggesting that iron dyshomeostasis worsens as cognitive impairment increases. Unlike Aß peptides, iron and iron-related proteins showed significant association with cognitive assessment tests, neuroimaging, and clinical data. Hepcidin and iron-related proteins comprise a group of serum biomarkers that relate to AD diagnosis and AD disease progression. Future studies should determine whether strategies targeted to diminishing hepcidin synthesis/secretion and improving iron homeostasis could have a beneficial impact on AD progression.

Relationship between Inflammation and Aspirin and Clopidogrel Antiplatelet Responses in Acute Ischemic Stroke.

OBJECTIVE: We measured serum levels of proinflammatory/prothrombotic markers P-selectin, CD40L, matrix metalloproteinase 9 (MMP-9), intracellular adhesion molecule 1 (ICAM-1), and interleukin (IL)-6 in ischemic stroke patients, correlating their levels with the results of aspirin (ASA) and clopidogrel antiplatelet responses, using 3 "point of care" platelet function instruments, thromboelastograph (TEG), Accumetrics (ACU), and impedance aggregometer (IMP). METHODS: Patients on chronic ASA regimen at the time of stroke were switched to 300 mg clopidogrel loading dose and 75 mg clopidogrel maintenance dose. Serum levels of the aforementioned inflammatory mediators were measured in 51 patients at baseline (on ASA regimen), and at 26 ± 5 hours and 64 ± 18 hours postclopidogrel administration by enzyme-linked immunosorbent assay. RESULTS: P-selectin, CD40L, and MMP-9 serum levels were reduced; ICAM-1 and IL-6 serum levels showed no difference postclopidogrel administration relative to baseline. Patients' stratification based on ASA dose showed more significant reductions in P-selectin, CD40L, and MMP-9 serum levels postclopidogrel administration in patients who were on baseline 81 mg ASA, as compared to patients on 325 mg ASA. Measurement with TEG was sensitive for correlating ASA antiplatelet responses to serum levels of inflammatory markers, whereas measurements with ACU and IMP were sensitive for correlating clopidogrel antiplatelet responses to serum levels of inflammatory markers. CONCLUSION: Clopidogrel exerts both platelet-dependent and platelet-independent anti-inflammatory effects. The association between platelet function and inflammation depends on the platelet function analyzer, the type of antiplatelet agent, the nature of the inflammatory marker, and the time of measurement relative to the time of drug administration.

High-mobility group box 1 in multiple sclerosis.

This study is one in series determining the potential of RAGE axis (receptor for advanced glycation end products, isoforms, ligands) as a biomarker in multiple sclerosis (MS). We evaluated serum levels of RAGE ligand, the high-mobility group box (HMGB)1 in MS patients, and assessed the correlation between HMGB1 serum levels and the use of disease-modifying drugs (DMDs), and between HMGB1 serum levels and indicators of MS disease severity. HMGB1 serum levels were compared between 96 (23 males) MS patients and 34 age- and gender-matched healthy controls (HCs) using enzyme-linked immunosorbent assays. DMD-naïve MS patients had significantly higher HMGB1 serum levels compared with DMD-treated (P = 0.04) and compared with HCs (P = 0.01). HMGB1 serum levels were not significantly different between total MS patients (DMD-naïve plus DMD-treated) and HCs (P = 0.09). DMD-naïve MS patients in clinical relapse tended to have lower HMGB1 serum levels than clinically stable RRMS patients (P = 0.07). HMGB1 serum levels showed 0.65 area under the curve (95 % CI 0.55-0.95) sensitivity/specificity for MS clinical relapse. The role of HMGB1 in MS disease pathology and DMD modulation of this protein warrant further investigations.

Enhancing Cognitive Abilities with Comprehensive Training: A Large, Online, Randomized, Active-Controlled Trial.

BACKGROUND: A variety of studies have demonstrated gains in cognitive ability following cognitive training interventions. However, other studies have not shown such gains, and questions remain regarding the efficacy of specific cognitive training interventions. Cognitive training research often involves programs made up of just one or a few exercises, targeting limited and specific cognitive endpoints. In addition, cognitive training studies typically involve small samples that may be insufficient for reliable measurement of change. Other studies have utilized training periods that were too short to generate reliable gains in cognitive performance. METHODS: The present study evaluated an online cognitive training program comprised of 49 exercises targeting a variety of cognitive capacities. The cognitive training program was compared to an active control condition in which participants completed crossword puzzles. All participants were recruited, trained, and tested online (N = 4,715 fully evaluable participants). Participants in both groups were instructed to complete one approximately 15-minute session at least 5 days per week for 10 weeks. RESULTS: Participants randomly assigned to the treatment group improved significantly more on the primary outcome measure, an aggregate measure of neuropsychological performance, than did the active control group (Cohen's d effect size = 0.255; 95% confidence interval = [0.198, 0.312]). Treatment participants showed greater improvements than controls on speed of processing, short-term memory, working memory, problem solving, and fluid reasoning assessments. Participants in the treatment group also showed greater improvements on self-reported measures of cognitive functioning, particularly on those items related to concentration compared to the control group (Cohen's d = 0.249; 95% confidence interval = [0.191, 0.306]). CONCLUSION: Taken together, these results indicate that a varied training program composed of a number of tasks targeted to different cognitive functions can show transfer to a wide range of untrained measures of cognitive performance. TRIAL REGISTRATION: ClinicalTrials.gov NCT-02367898.

Evidence for age-associated cognitive decline from Internet game scores.

INTRODUCTION: Lumosity's Memory Match (LMM) is an online game requiring visual working memory. Change in LMM scores may be associated with individual differences in age-related changes in working memory. METHODS: Effects of age and time on LMM learning and forgetting rates were estimated using data from 1890 game sessions for users aged 40 to 79 years. RESULTS: There were significant effects of age on baseline LMM scores (ß = -.31, standard error or SE = .02, P < .0001) and lower learning rates (ß = -.0066, SE = .0008, P < .0001). A sample size of 202 subjects/arm was estimated for a 1-year study for subjects in the lower quartile of game performance. DISCUSSION: Online memory games have the potential to identify age-related decline in cognition and to identify subjects at risk for cognitive decline with smaller sample sizes and lower cost than traditional recruitment methods.

Disease modifying drugs modulate endogenous secretory receptor for advanced glycation end-products, a new biomarker of clinical relapse in multiple sclerosis.

OBJECTIVES: This study is one in a series measuring RAGE axis (receptor for advanced glycation end products, its isoforms, and ligands) and its potential as a biomarker in multiple sclerosis (MS). We evaluated serum levels of the endogenous secretory RAGE (esRAGE) in MS patients and assessed the relationship between esRAGE levels and the use of disease modifying drugs (DMDs), and between esRAGE levels and indicators of MS disease severity. METHOD: esRAGE serum levels were compared between 98 MS patients and 34 healthy controls (HCs) using ELISA. RESULTS: esRAGE serum levels were similar between MS and HCs. DMD-treated patients had higher esRAGE serum levels than DMD-naïve patients (395.7±38.6pg/ml vs. 299.2±20.1pg/ml, P=0.02). DMD-naïve, primary progressive (PP) patients had higher esRAGE serum levels, than relapsing remitting (RR) (P=0.02) and secondary progressive (SP) (P=0.04) patients; RRMS patients in clinical relapse had lower esRAGE serum levels than clinically stable patients (219.7±30.0pg/ml vs. 338.2±31.6pg/ml, P=0.02). In a univariate regression analysis of DMD-naïve MS patients, esRAGE serum levels inversely correlated with the rate of clinical relapse (r=-0.44, P=0.006), MS severity scale (MSSS) (r=-0.32, P=0.03), and expanded disability status scale (EDSS) (r=-0.251, P=0.07). CONCLUSION: esRAGE serum levels are modulated by DMDs. The serum levels may be a useful biomarker of MS clinical relapse.

Disease modifying therapies modulate cardiovascular risk factors in patients with multiple sclerosis.

OBJECTIVES: This retrospective study aimed to determine (1) the association between the use of three major disease modifying therapies (DMTs) (Interferon-beta [IFN-ß], Glatiramer acetate [GA], Natalizumab [NTZ]) and cardiovascular (CV) risk factors in multiple sclerosis (MS) patients, and (2) the association between the use of CV drugs (antihypertensive, hypolipidemic, and antiplatelets) and other drugs acting on the CV system (antispastics/anticonvulsants/anxyolitics, antidepressants/stimulants), and MS disease severity. METHODS: The charts of 188 patients with MS, who were taking one of the three DMTs, and 110 patients, who were naïve to these drugs, were retrospectively reviewed. The obtained data included height and weight, fasting lipid profiles, plasma glucose, systolic and diastolic BP, smoking habit, list of medications, and indicators of MS disease severity. RESULTS: The use of DMTs was associated with higher diastolic BP readings, as well as higher plasma glucose and HDL-C plasma levels. In addition, there was an association between CV risk factors and the type of DMTs. When compared to DMT-naïve patients with MS, the use of IFN-ß and GA was associated with higher CV risk factors, whereas the use of NTZ was associated with lower CV risk factors. In DMT-naïve patients, the use of CV and related drugs was associated with higher Extended Disability Status Scale (EDSS) and higher MS Severity Scale (MSSS). CONCLUSION: There is an association between higher CV risk factors and the use of DMTs. Furthermore, CV and related drugs have the potential for modulating MS disease severity.

Quantitative and qualitative pleiotropic differences between Simvastatin single and Vytorin combination therapy in hypercholesterolemic subjects.

AIMS: This cross-sectional study tested the hypothesis that treatment with the combination of Ezetimibe/Simvastatin (Vytorin) leads to broader changes in the expression levels of immunomodulatory genes as compared to Simvastatin monotherapy. METHODS: Illumina's GenomeStudio gene expression module was used to compare gene profiles of Vytorin and Simvastatin in the peripheral blood mononuclear cells of 20 hypercholesterolemic subjects. RESULTS: The characteristics of the immunomodulatory genes, which were altered by Vytorin, differed from those genes which were altered by Simvastatin. Vytorin mostly altered the expression levels of genes related to inflammation/oxidative stress; it downregulated the NF-KappaB and upregulated the expression of anti-inflammatory cytokine, IL-10, and anti-oxidant enzymes, GPX1 and SOD2, but also upregulated the expression levels of genes involved in cellular activation, adhesion, and coagulation cascade, including VWF, F7, PF4, PF4V1 SELP, ITGB3, ITGB5. Simvastatin mostly altered the expression levels of genes related to cellular apoptosis/proliferation. It upregulated the expression levels of apoptosis-related genes APAF1, BAX, IER3, and CSF1R, and downregulated the expression levels of genes related to cellular proliferation, including PTN and CD69. Treatment with Vytorin combination therapy modulated lipid profile and serum levels of the C-reactive protein more effectively, than treatment with Simvastatin monotherapy. CONCLUSION: The nature of the pleiotropic effects may play a role in Vytorin's and Simvastatin's clinical efficacies.

Prevalence of eosinophilic esophagitis in children with refractory aerodigestive symptoms.

IMPORTANCE: Eosinophilic esophagitis (EoE) is an increasingly important diagnosis for children; it has a remarkable impact on their quality of life and can present with aerodigestive symptoms commonly evaluated by otolaryngologists. OBJECTIVES: To evaluate the prevalence of EoE in children presenting to a pediatric aerodigestive clinic, to describe their presentation, and to review the role of subsequent food allergy evaluation and treatment. DESIGN: Review of a prospective database. SETTING: Tertiary pediatric multispecialty aerodigestive center. PATIENTS: Children with aerodigestive symptoms refractory to medical treatment who underwent direct laryngoscopy with rigid or flexible bronchoscopy and esophagoscopy with or without pH probe study. MAIN OUTCOMES AND MEASURES: Diagnosis of EoE. RESULTS: Between 2003 and 2012, 376 of 1540 children seen in the center (mean [range] age, 4.54 [0-18.6] years; male to female ratio, 1.72:1) remained symptomatic despite medical therapy and thus underwent triple endoscopic evaluation. Of the 376 children, 14 (3.7%) were eventually diagnosed as having EoE, as defined by 15 or more eosinophils per high-power field on esophageal biopsy and either a negative pH study result or nonresponse to a trial of high-dose proton pump inhibitors. The subpopulation with EoE presented with airway symptoms and diagnoses, most commonly cough (n = 6; 42.9%). Inflammatory subglottic stenosis due to EoE was identified in 1 patient. Of the 14 children with EoE, 6 presented with gastrointestinal symptomatology, most commonly choking or gagging. Subsequent treatment including food allergy challenge and elimination diet resulted in a clinical improvement in half of the cases identified. CONCLUSIONS AND RELEVANCE: This represents the largest multispecialty clinic epidemiologic study evaluating the prevalence of EoE in children presenting not strictly with gastrointestinal symptoms but rather with aerodigestive symptoms that are frequently evaluated by pediatric otolaryngologists. Although the prevalence is low, EoE should be considered for children with appropriate symptoms in whom other medical therapies fail.

The largest human cognitive performance dataset reveals insights into the effects of lifestyle factors and aging.

Making new breakthroughs in understanding the processes underlying human cognition may depend on the availability of very large datasets that have not historically existed in psychology and neuroscience. Lumosity is a web-based cognitive training platform that has grown to include over 600 million cognitive training task results from over 35 million individuals, comprising the largest existing dataset of human cognitive performance. As part of the Human Cognition Project, Lumosity's collaborative research program to understand the human mind, Lumos Labs researchers and external research collaborators have begun to explore this dataset in order uncover novel insights about the correlates of cognitive performance. This paper presents two preliminary demonstrations of some of the kinds of questions that can be examined with the dataset. The first example focuses on replicating known findings relating lifestyle factors to baseline cognitive performance in a demographically diverse, healthy population at a much larger scale than has previously been available. The second example examines a question that would likely be very difficult to study in laboratory-based and existing online experimental research approaches at a large scale: specifically, how learning ability for different types of cognitive tasks changes with age. We hope that these examples will provoke the imagination of researchers who are interested in collaborating to answer fundamental questions about human cognitive performance.

The prevalence of the classical and non-classical cardiovascular risk factors in multiple sclerosis patients.

BACKGROUND: Inflammation is known to play a role in cererovascular risk. Multiple sclerosis (MS) is a neurodegenerative disease that is initially characterized by inflammatory changes in the brain. We hypothesized that due to chronic inflammation, MS patients would present with a higher levels of cardiovascular (CV) risk factors than non-MS patients. METHODS: We performed a retrospective chart review on 206 MS patients and 142 control patients suffering from meningiomas and acoustic neuromas, non inflammatory, non autoimmune diseases of the brain. The obtained data included fasting lipid profiles, plasma glucose, systolic and diastolic blood pressure (BP), serum levels of homocysteine and uric acid, data on iron status, smoking habit, and list of medications. In addition, data on indicators of MS disease severity was obtained for MS patients. RESULTS: MS patients had significantly higher total plasma cholesterol, p = 0.01, and plasma high density lipoprotein, P < 0.001, but lower plasma glucose, P < 0.001, and systolic BP, P = 0.001, than non-MS patients. In addition, MS patients had lower erythrocyte sedimentation rate and serum vitamin B12, but higher serum folic acid and vitamin D3 than non-MS patients. A positive correlation was observed between plasma glucose and the extended disability status scale (EDSS), P = 0.008, and between plasma glucose and the rate of clinical relapse, P = 0.001. CONCLUSION: The MS pathophysiology may be among factors for the lower CV risk factors in MS patients. Future studies should examine whether the chronic use of many pharmacological agents influence CV risk factors in MS patients.

Lp-PLA2: inflammatory biomarker of vascular risk in multiple sclerosis.

A member of the A2 phospholipase superfamily, the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2), is involved in atherogenic processes. Lp-PLA2 mass and activity were measured by the enzyme-linked immunosorbent assay and by a colorimetric method, respectively, and compared among 63 multiple sclerosis (MS) patients and 47 age-matched healthy controls (HCs). Lp-PLA2 plasma levels were significantly higher in MS patients (236.7 ± 10 ng/ml) compared to HCs (197.0 ± 7 ng/ml) (p = 0.003), but LP-PLA2 activity did not differ between the two groups. Both Lp-PLA2 plasma mass and activity were higher in secondary progressive (mass 247.0 ±15.5 ng/ml, p = 0.05; activity 156.1 ±6 nmol/min/ml, p = 0.003) compared to relapsing-remitting MS patients (mass 227.0 ± 16 ng/ml; activity 128.8 ± 5 nmol/min/ml) and compared to HCs. Lp-PLA2 plasma activity was associated with measures of MS clinical disability. However, this association was attenuated after adjustment for the components of lipid profiles.

Two mechanisms of human contingency learning.

How do humans learn contingencies between events? Both pathway-strengthening and inference-based process models have been proposed to explain contingency learning. We propose that each of these processes is used in different conditions. Participants viewed displays that contained single or paired objects and learned which displays were usually followed by the appearance of a dot. Some participants predicted whether the dot would appear before seeing the outcome, whereas other participants were required to respond quickly if the dot appeared shortly after the display. In the prediction task, instructions guiding participants to infer which objects caused the dot to appear were necessary in order for contingencies associated with one object to influence participants' predictions about the object with which it had been paired. In the response task, contingencies associated with one object affected responses to its pair mate irrespective of whether or not participants were given causal instructions. Our results challenge single-mechanism accounts of contingency learning and suggest that the mechanisms underlying performance in the two tasks are distinct.

Plasma pentosidine: a potential biomarker in the management of multiple sclerosis.

BACKGROUND: The chronic inflammation associated with multiple sclerosis (MS) may lead to the upregulation of pentosidine. OBJECTIVES: This cross-sectional study compares plasma pentosidine levels among healthy controls (HCs) and patients with MS at different disease stages. The study also determines pentosidine's usefulness as a biomarker of MS disease activity and/or severity via its correlation with a number of indicators of MS disease. METHODS: Pentosidine levels were analyzed in 98 MS patients and 43 HCs using reverse-phase high-pressure liquid chromatography with fluorescence detection. RESULTS: Plasma pentosidine levels were significantly higher in MS patients when compared with HCs (p = 0.02). Patients on disease-modifying therapies (DMTs) had lower plasma pentosidine levels when compared with DMT-naïve patients (p = 0.01). Pentosidine plasma levels correlated with indicators of MS disease severity, including Extended Disability Status Scale (p = 0.03), MS Severity Scale (p = 0.01), and MS Functional Composite (p = 0.03). No correlation between pentosidine levels and age, rate of clinical relapse, and disease duration was observed. CONCLUSIONS: Our results suggest that pentosidine could be a novel, inflammatory biomarker in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma pentosidine levels and MS disease pathology. These studies may pave the way for use of advanced glycation end product (AGE) inhibitors and AGE-breaking agents as new therapeutic modalities in MS.

Diagnostic potential of plasma carboxymethyllysine and carboxyethyllysine in multiple sclerosis.

BACKGROUND: This study compared the level of advanced glycation end products (AGEs), N-(Carboxymethyl)lysine (CML) and N-(Carboxyethyl)lysine (CEL), in patients with multiple sclerosis (MS) and healthy controls (HCs), correlating these markers with clinical indicators of MS disease severity. METHODS: CML and CEL plasma levels were analyzed in 99 MS patients and 43 HCs by tandem mass spectrometry (LC/MS/MS). Patients were stratified based on drug modifying therapies (DMTs) including interferon beta, glatiramer acetate and natalizumab. RESULTS: The level of plasma CEL, but not CML, was significantly higher in DMT-naïve MS patients when compared to HCs (P < 0.001). Among MS patients, 91% had higher than mean plasma CEL observed in HCs. DMTs reduced CML and CEL plasma levels by approximately 13% and 40% respectively. CML and CEL plasma levels correlated with the rate of MS clinical relapse. CONCLUSION: Our results suggest that AGEs in general and CEL in particular could be useful biomarkers in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma level of AGEs and MS disease pathology. These studies will pave the way for use of AGE inhibitors and AGE-breaking agents as new therapeutic modalities in MS.

A connectionist approach to embodied conceptual metaphor.

A growing body of data has been gathered in support of the view that the mind is embodied and that cognition is grounded in sensory-motor processes. Some researchers have gone so far as to claim that this paradigm poses a serious challenge to central tenets of cognitive science, including the widely held view that the mind can be analyzed in terms of abstract computational principles. On the other hand, computational approaches to the study of mind have led to the development of specific models that help researchers understand complex cognitive processes at a level of detail that theories of embodied cognition (EC) have sometimes lacked. Here we make the case that connectionist architectures in particular can illuminate many surprising results from the EC literature. These models can learn the statistical structure in their environments, providing an ideal framework for understanding how simple sensory-motor mechanisms could give rise to higher-level cognitive behavior over the course of learning. Crucially, they form overlapping, distributed representations, which have exactly the properties required by many embodied accounts of cognition. We illustrate this idea by extending an existing connectionist model of semantic cognition in order to simulate findings from the embodied conceptual metaphor literature. Specifically, we explore how the abstract domain of time may be structured by concrete experience with space (including experience with culturally specific spatial and linguistic cues). We suggest that both EC researchers and connectionist modelers can benefit from an integrated approach to understanding these models and the empirical findings they seek to explain.