A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants.

Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2-C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2-C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30-50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2-C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H+-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2-C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.

The Population Attributable Fraction of Dementia From Audiometric Hearing Loss Among a Nationally Representative Sample of Community-Dwelling Older Adults.

BACKGROUND: The population attributable fraction (PAF) of dementia from hearing loss (HL) in the United States is ~2% when incorporating self-reported HL measures. However, self-report might underestimate clinically significant audiometric HL among older adults. Here, we quantified PAFs of dementia from audiometric HL overall and by age, sex, and race/ethnicity groups among a nationally representative sample of community-dwelling older adults in the United States. METHODS: We used cross-sectional data from Round 11 (2021) of the National Health and Aging Trends Study, a prospective cohort study representing the U.S. Medicare population aged 65+ years (N = 2 470). We estimated model-adjusted PAFs of prevalent dementia by audiometric HL (pure-tone averages: normal hearing, <26 dB HL; mild HL, 26-40 dB HL; moderate or greater HL, ≥41 dB HL). RESULTS: Among eligible participants (34.8% aged ≥80 years; 55.3% female; 82.4% non-Hispanic White), 37.5% had mild, and 28.8% had moderate or greater HL. Dementia prevalence overall was 10.6%, with the PAF predominately driven by moderate or greater HL (PAF = 16.9%; 95% confidence interval [CI]: 4.1-28.7%). The PAF from any degree of HL was larger but with a wider CI (PAF = 18.7%, 95% CI: -5.3% to 40.1%). There was evidence associations differed by sex but not age or race/ethnicity; moderate or greater HL exhibited stronger associations among males (PAF = 40.5%; 95% CI: 19.5% to 57.2%) than females (PAF = 3.2%; 95% CI: -12.7% to 17.9%). CONCLUSIONS: In a nationally representative sample of community-dwelling older adults in the United States, 17% of dementia cases were attributable to moderate or greater audiometric HL, an estimate that is eightfold higher relative to studies relying on self-reported hearing measures only.

Inclusion of hearing and vision impairments in cognitive training interventions.

Introduction: Cognitive training can potentially reduce risk of cognitive decline and dementia in older adults. To support implementation of cognitive training in the broader population of older adults, it is critical to evaluate intervention implementation and efficacy among representative samples, particularly those at highest risk of cognitive decline. Hearing and vision impairments are highly prevalent among older adults and confer increased risk of cognitive decline/dementia. Whether cognitive training interventions enroll and are designed to include this important subgroup is unknown. Methods: A scoping review of PubMed and PsycINFO was conducted to examine the inclusion of older adults with hearing and vision impairment in cognitive training interventions. Two independent reviewers completed a full-text review of eligible articles. Eligible articles included cognitive training and multimodal randomized controlled trials and a study population that was cognitively unimpaired, aged ≥55-years, and community dwelling. Articles were primary outcome papers published in English. Results: Among the 130 articles included in the review, 103 were cognitive training interventions (79%) and 27 were multimodal interventions (21%). More than half the trials systematically excluded participants with hearing and/or vision impairment (n = 60, 58%). Few studies reported hearing and vision measurement (cognitive: n = 16, 16%; multimodal: n = 3, 11%) or incorporated universal design and accessibility into intervention design (cognitive: n = 7, 7%; multimodal: n = 0, 0%). Discussion: Older adults with hearing and vision impairment are underrepresented in cognitive training interventions. Reporting of hearing and vision measurement, proper justification of exclusions, and inclusion of accessibility and universal intervention design are also lacking. These findings raise concerns about whether current trial findings apply to those with hearing and vision impairment and generalize to the broader population of older adults. It is critical to include more diverse study populations and integrate accessibility into intervention design to include and better represent older adults with hearing and vision impairment. Highlights: Cognitive training interventions underrepresent hearing and vision impairment.Sensory measurement and proper justification of exclusions are rarely reported.Interventions lack inclusion of accessibility and universal intervention design.More diverse study populations are needed in cognitive training interventions.Integration of accessibility into cognitive training intervention design is needed.

Large-Scale Virtual Screening for the Discovery of SARS-CoV-2 Papain-like Protease (PLpro) Non-covalent Inhibitors.

The rapid global spread of the SARS-CoV-2 virus facilitated the development of novel direct-acting antiviral agents (DAAs). The papain-like protease (PLpro) has been proposed as one of the major SARS-CoV-2 targets for DAAs due to its dual role in processing viral proteins and facilitating the host's immune suppression. This dual role makes identifying small molecules that can effectively neutralize SARS-CoV-2 PLpro activity a high-priority task. However, PLpro drug discovery faces a significant challenge due to the high mobility and induced-fit effects in the protease's active site. Herein, we virtually screened the ZINC20 database with Deep Docking (DD) to identify prospective noncovalent PLpro binders and combined ultra-large consensus docking with two pharmacophore (ph4)-filtering strategies. The analysis of active compounds revealed their somewhat-limited diversity, likely attributed to the induced-fit nature of PLpro's active site in the crystal structures, and therefore, the use of rigid docking protocols poses inherited limitations. The top hits were assessed against recombinant viral proteins and live viruses, demonstrating desirable inhibitory activities. The best compound VPC-300195 (IC50: 15 µM) ranks among the top noncovalent PLpro inhibitors discovered through in silico methodologies. In the search for novel SARS-CoV-2 PLpro-specific chemotypes, the identified inhibitors could serve as diverse templates for the development of effective noncovalent PLpro inhibitors.

Dementia occurring over a 32-year follow-up attributable to hypertension observed at different ages: Implications for dementia prevention.

INTRODUCTION: The fraction of dementia attributable to hypertension might vary depending on the age of the population considered and the age through which dementia occurs. METHODS: In the Atherosclerosis Risk in Communities study, we quantified population attributable fractions (PAF) of dementia by age 80 and 90 from hypertension assessed at ages of 45-54 (n = 7572), 55-64 (n = 12,033), 65-74 (n = 6561), and 75-84 (n = 2086). RESULTS: The PAF for dementia by age 80 from all non-normal blood pressure at ages 45-54 was 15.3% (95% confidence interval [CI] = 6.9%-22.3%), 19.1% (95% CI = 9.9%-26.9%) at ages 55-64, and 19.9% (95% CI = -4.4%-38.5%) at ages 65-74. The strongest PAFs were from stage 2 hypertension (11.9%-21.3%). For dementia by age 90, PAFs from non-normal blood pressure up through age 75 were smaller (10.9%-13.8%), and non-significant by age 75-84. DISCUSSION: Interventions targeting hypertension even in early late life might reduce a sizeable proportion of dementia. HIGHLIGHTS: We estimated prospective population attributable risks of dementia for hypertension. 15%-20% of dementia cases by age 80 are from non-normal blood pressure (BP). Associations between hypertension and dementia persisted through age 75. Midlife to early late-life BP control might reduce a large proportion of dementia.

Shifting of Cognitive Assessments Between Face-to-Face and Telephone Administration: Measurement Considerations.

OBJECTIVES: Telephone-administered cognitive assessments are a cost-effective and sometimes necessary alternative to face-to-face assessments. There is limited information in large studies concerning mode effects, or differences in cognition attributable to the assessment method, as a potential measurement threat. We evaluated mode effects on cognitive scores using a population-based sample of community-living older adults. METHODS: We used data from participants aged 65-79 in the 2014 Health and Retirement Study for whom the interview mode was randomized (n = 6,825). We assessed mode differences in test means, whether mode modifies associations of cognition with criterion variables, and formal measurement invariance testing. RESULTS: Relative to face-to-face assessment, telephone assessment was associated with higher scores for memory and calculation (0.06 to 0.013 standard deviations [SD]) and lower scores for nonmemory items (-0.09 to -0.01 SD). Cognition was significantly differentially related to instrumental activities of daily living difficulty depending on assessment mode. Measurement invariance testing identified evidence of mode differences in certain tests as a function of mode: adjusting for underlying cognition, the largest mode differences in memory and attention: immediate noun recall, delayed word recall, and serial-7s scores were higher given telephone administration. DISCUSSION: Differences by mode of administration are apparent in cognitive measurement in older adults, albeit to a small degree in our study, and most pronounced for tests of memory and attention. The importance of accounting for mode differences ultimately depends on one's research question and study sample: not all associations may be affected by mode differences, and such modification may only be apparent among those with lower cognitive functioning.

Self-Reported Dual Sensory Impairment and Subjective Cognitive Complaints Among Older Adults in the 2019 National Health Interview Survey.

PURPOSE: Subjective cognitive complaints (SCCs) are associated with poor quality of life, important for clinical care planning and management, and may predict dementia diagnosis. Dual sensory impairment (DSI) is a risk factor for dementia, but whether DSI is associated with SCCs is unknown. We evaluated whether self-reported DSI is associated with SCCs. METHOD: We performed a cross-sectional analysis of 9,899 community-dwelling respondents aged 60+ years without dementia or depression in the 2019 National Health Interview Survey. Participants self-reported difficulty remembering or concentrating, seeing even when wearing corrective lenses, and hearing even when using a hearing aid. We defined SCCs and sensory impairment for each mode as reporting at least some difficulty. We categorized sensory impairment into no sensory impairment, vision impairment only, hearing impairment only, and DSI. We then estimated weighted prevalence ratios (PRs) of SCCs by impairment category. RESULTS: After weighting (9,899 participants representing a weighted n = 59,261,749), 12% of participants reported vision impairment only, 19% reported hearing impairment only, and 7% reported DSI. Relative to no impairment, after adjustment for potential confounders, vision impairment (PR = 2.07; 95% confidence interval [CI] [1.79, 2.39]), hearing impairment (PR = 2.26; 95% CI [2.00, 2.55]), and DSI (PR = 3.21; 95% CI [2.83, 3.63]) were associated with an increased prevalence of SCCs. CONCLUSIONS: In this nationally representative survey of older Americans, DSI was associated with a threefold increased prevalence of SCCs. Although cross-sectional, these data underscore the importance of assessing multiple impairments as exposures when studying subjective cognition in older adults. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21498711.

Targeting SARS-CoV-2 papain-like protease in the postvaccine era.

While vaccines remain at the forefront of global healthcare responses, pioneering therapeutics against SARS-CoV-2 are expected to fill the gaps for waning immunity. Rapid development and approval of orally available direct-acting antivirals targeting crucial SARS-CoV-2 proteins marked the beginning of the era of small-molecule drugs for COVID-19. In that regard, the papain-like protease (PLpro) can be considered a major SARS-CoV-2 therapeutic target due to its dual biological role in suppressing host innate immune responses and in ensuring viral replication. Here, we summarize the challenges of targeting PLpro and innovative early-stage PLpro-specific small molecules. We propose that state-of-the-art computer-aided drug design (CADD) methodologies will play a critical role in the discovery of PLpro compounds as a novel class of COVID-19 drugs.

Seizure Prophylaxis After Spontaneous Intracerebral Hemorrhage.

Importance: Limited evidence is available concerning optimal seizure prophylaxis after spontaneous intracerebral hemorrhage (sICH). Objective: To evaluate which of 4 seizure prophylaxis strategies provides the greatest net benefit for patients with sICH. Design, Setting, and Participants: This decision analysis used models to simulate the following 4 common scenarios: (1) a 60-year-old man with low risk of early (≤7 days after stroke) (10%) and late (3.6% or 9.8%) seizures and average risk of short- (9%) and long-term (30%) adverse drug reaction (ADR); (2) an 80-year-old woman with low risk of early (10%) and late (3.6% or 9.8%) seizures and high short- (24%) and long-term (80%) ADR risks; (3) a 55-year-old man with high risk of early (19%) and late (34.8% or 46.2%) seizures and low short- (9%) and long-term (30%) ADR risks; and (4) a 45-year-old woman with high risk of early (19%) and late (34.8% or 46.2%) seizures and high short- (18%) and long-term (60%) ADR risks. Interventions: The following 4 antiseizure drug strategies were included: (1) conservative, consisting of short-term (7-day) secondary early-seizure prophylaxis with long-term therapy after late seizure; (2) moderate, consisting of long-term secondary early-seizure prophylaxis or late-seizure therapy; (3) aggressive, consisting of long-term primary prophylaxis; and (4) risk guided, consisting of short-term secondary early-seizure prophylaxis among low-risk patients (2HELPS2B score, 0), short-term primary prophylaxis among patients at higher risk (2HELPS2B score, ≥1), and long-term secondary therapy for late seizure. Main Outcomes and Measures: Quality-adjusted life-years (QALYs). Results: For scenario 1, the risk-guided strategy (8.13 QALYs) was preferred over the conservative (8.08 QALYs), moderate (8.07 QALYs), and aggressive (7.88 QALYs) strategies. For scenario 2, the conservative strategy (2.18 QALYs) was preferred over the risk-guided (2.17 QALYs), moderate (2.09 QALYs), and aggressive (1.15 QALYs) strategies. For scenario 3, the aggressive strategy (9.21 QALYs) was preferred over the risk-guided (8.98 QALYs), moderate (8.93 QALYs), and conservative (8.77 QALYs) strategies. For scenario 4, the risk-guided strategy (11.53 QALYs) was preferred over the conservative (11.23 QALYs), moderate (10.93 QALYs), and aggressive (8.08 QALYs) strategies. Sensitivity analyses suggested that short-term strategies (conservative and risk guided) are preferred under most scenarios, and the risk-guided strategy performs comparably to or better than alternative strategies in most settings. Conclusions and Relevance: This decision analytical model suggests that short-term (7-day) prophylaxis dominates longer-term therapy after sICH. Use of the 2HELPS2B score to guide clinical decisions for initiation of short-term primary vs secondary early-seizure prophylaxis should be considered for all patients after sICH.

Modification of amyloid-beta peptide aggregation via photoactivation of strained Ru(ii) polypyridyl complexes.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive and irreversible damage to the brain. One of the hallmarks of the disease is the presence of both soluble and insoluble aggregates of the amyloid beta (Aß) peptide in the brain, and these aggregates are considered central to disease progression. Thus, the development of small molecules capable of modulating Aß peptide aggregation may provide critical insight into the pathophysiology of AD. In this work we investigate how photoactivation of three distorted Ru(ii) polypyridyl complexes (Ru1-3) alters the aggregation profile of the Aß peptide. Photoactivation of Ru1-3 results in the loss of a 6,6'-dimethyl-2,2'-bipyridyl (6,6'-dmb) ligand, affording cis-exchangeable coordination sites for binding to the Aß peptide. Both Ru1 and Ru2 contain an extended planar imidazo[4,5-f][1,10]phenanthroline ligand, as compared to a 2,2'-bipyridine ligand for Ru3, and we show that the presence of the phenanthroline ligand promotes covalent binding to Aß peptide His residues, and in addition, leads to a pronounced effect on peptide aggregation immediately after photoactivation. Interestingly, all three complexes resulted in a similar aggregate size distribution at 24 h, forming insoluble amorphous aggregates as compared to significant fibril formation for peptide alone. Photoactivation of Ru1-3 in the presence of pre-formed Aß1-42 fibrils results in a change to amorphous aggregate morphology, with Ru1 and Ru2 forming large amorphous aggregates immediately after activation. Our results show that photoactivation of Ru1-3 in the presence of either monomeric or fibrillar Aß1-42 results in the formation of large amorphous aggregates as a common endpoint, with Ru complexes incorporating the extended phenanthroline ligand accelerating this process and thereby limiting the formation of oligomeric species in the initial stages of the aggregation process that are reported to show considerable toxicity.

Anticonvulsant Primary and Secondary Prophylaxis for Acute Ischemic Stroke Patients: A Decision Analysis.

Background and Purpose: We examined the impact of 3 anticonvulsant prophylaxis strategies on quality-adjusted life-years (QALYs) among patients with an incident acute ischemic stroke. Methods: We created a decision tree to evaluate 3 strategies: (1) long-term primary prophylaxis; (2) short-term secondary prophylaxis after an early seizure with lifetime prophylaxis if persistent or late seizures (LSs) developed; and (3) long-term secondary prophylaxis if either early, late, or persistent seizures developed. The outcome was quality-adjusted life expectancy (QALY). We created 4 base cases to simulate common clinical scenarios: (1) female patient aged 40 years with a 2% or 11% lifetime risk of an LS and a 33% lifetime risk of an adverse drug reaction (ADR); (2) male patient aged 65 years with a 6% or 29% LS risk and 60% ADR risk; (3) male patient aged 50 years with an 18% or 65% LS risk and 33% ADR risk; and (4) female patient aged 80 years with a 29% or 83% LS risk and 80% ADR risk. In sensitivity analyses, we altered the parameters and assumptions. Results: Across all 4 base cases, primary prophylaxis yielded the fewest QALYs when compared with secondary prophylaxis. For example, under scenario 1, strategies 2 and 3 resulted in 7.17 QALYs each, but strategy 1 yielded only 6.91 QALYs. Under scenario 4, strategies 2 and 3 yielded 2.85 QALYs compared with 1.40 QALYs for strategy 1. Under scenarios in which patients had higher ADR risks, strategy 2 led to the most QALYs. Conclusions: Short-term therapy with continued anticonvulsant prophylaxis only after postischemic stroke seizures arise dominates lifetime primary prophylaxis in all scenarios examined. Our findings reinforce the necessity of close follow-up and discontinuation of anticonvulsant seizure prophylaxis started during acute ischemic stroke hospitalization.

Exposure to Select Pathogens in an Expanding Moose (Alces alces) Population in North Dakota, USA.

Forty female moose (Alces alces) captured in North Dakota, US, in March 2014 were tested for antibodies to a variety of pathogens. Antibodies to West Nile virus (WNV) were detected in 39 (98%) moose following a year with a high number of human cases, suggesting the population accurately reflects WNV activity. Fifteen percent of moose (6/40) had antibodies to Borrelia burgdorferi, implying expansion of the tick vector into the area. Antibodies to Anaplasma spp. were detected in 55% of moose (22/40), a higher rate than previously detected in cattle from the region. Low titers (100-400) to one or more serovars of Leptospira spp. were detected in 23% of moose (9/40), a common finding in wild ruminants. Exposure to other pathogens was uncommon (<8%; <3/40) or not documented. Survival and recruitment were high during the study period, suggesting a limited population-level impact at current levels of exposure and environmental co-stressors.

Telemedicine Can Support Measurable and High-Quality Epilepsy Care During the COVID-19 Pandemic.

Routine outpatient epilepsy care has shifted from in-person to telemedicine visits in response to safety concerns posed by the coronavirus disease 2019 (COVID-19) pandemic. But whether telemedicine can support and maintain standardized documentation of high-quality epilepsy care remains unknown. In response, the authors conducted a quality improvement study at a level 4 epilepsy center between January 20, 2019, and May 31, 2020. Weekly average completion proportion of standardized documentation used by a team of neurologists for adult patients for the diagnosis of epilepsy, seizure classification, and frequency were analyzed. By December 15, 2019, a 94% average weekly completion proportion of standardized epilepsy care documentation was achieved that was maintained through May 31, 2020. Moreover, during the period of predominately telemedicine encounters in response to the pandemic, the completion proportion was 90%. This study indicates that high completion of standardized documentation of seizure-related information can be sustained during telemedicine appointments for routine outpatient epilepsy care at a level 4 epilepsy center.

Patterns of anticonvulsant use and adverse drug events in older adults.

PURPOSE: To examine indications for, duration of use, and rate of adverse drug events (ADE) attributable to anticonvulsant initiation, as adjudicated by expert review of electronic health records (EHR) of older adults. METHODS: We identified a cohort of community dwelling Medicare beneficiaries with linked EHR (aged 65+, continuously enrolled with a large health system/until death between 2012 and 2014, n = 20 945) and drew a stratified EHR review sample (n = 1534). An expert reviewed all records to adjudicate anticonvulsant use, years of use, indication for use, and evidence of ADEs attributable to anticonvulsant initiation. After excluding patients with insufficient EHR data (n = 37; 2%), we reconstructed the cohort using inverse probability weights to resemble the original cohort of eligible beneficiaries (n = 20 380). Among incident users of a single anticonvulsant, we estimated the rate of ADEs and described the type and severity of ADEs. RESULTS: Overall, 12% (n = 2469) of eligible beneficiaries used at least one anticonvulsant in the 2012 to 2014 period (4% [n = 757] incident users, 8% [n = 1712] prevalent users). Incident users were most frequently prescribed gabapentin (n = 461/757, 61%), benzodiazepines (n = 122/757, 16%), and levetiracetam (n = 74/757, 10%); the most common indication was pain relief (n = 214; 28%) followed by epilepsy (n = 53; 7%). Among incident users, the overall ADE rate was 10/100 person-years (95% CI 4-20/100 person-years), of which 29% (n = 28/97) were life threatening (eg, somnolence). Most ADEs among incident monotherapy users were nervous system related (68%, n = 66/97). CONCLUSION: Many older adult community dwelling traditional Medicare beneficiaries had clinically significant ADEs likely attributable to the initiation of anticonvulsant therapy, which was begun for a range of indications.

Accuracy of ICD-10-CM claims-based definitions for epilepsy and seizure type.

OBJECTIVE: To evaluate the accuracy of ICD-10-CM claims-based definitions for epilepsy and classifying seizure types in the outpatient setting. METHODS: We reviewed electronic health records (EHR) for a cohort of adults aged 18+ years seen by six neurologists who had an outpatient visit at a level 4 epilepsy center between 01/2019-09/2019. The neurologists used a standardized documentation template to capture the diagnosis of epilepsy (yes/no/unsure), seizure type (focal/generalized/unknown), and seizure frequency in the EHR. Using linked ICD-10-CM codes assigned by the provider, we assessed the accuracy of claims-based definitions for epilepsy, focal seizure type, and generalized seizure type against the reference-standard EHR documentation by estimating sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV). RESULTS: There were 673 eligible outpatient encounters. After review of EHRs for standardized documentation, an analytic sample consisted of 520 encounters representing 402 unique patients. In the EHR documentation, 93.5 % (n = 486/520) of encounters were with patients with a diagnosis of epilepsy. Of those, 66.0 % (n = 321/486) had ≥1 focal seizure, 41.6 % (n = 202/486) had ≥1 generalized seizure, and 7% (n = 34/486) had ≥1 unknown seizure. An ICD-10-CM definition for epilepsy (i.e., ICD-10 G40.X) achieved Sn = 84.4 % (95 % CI 80.8-87.5%), Sp = 79.4 % (95 % CI 62.1-91.3%), PPV = 98.3 % (95 % CI 96.6-99.3%), and NPV = 26.2 % (95 % CI 18.0-35.8%). The classification of focal vs generalized/unknown seizures achieved Sn = 69.8 % (95 % CI 64.4-74.8%), Sp = 79.4 % (95 % CI 72.4-85.3%), PPV = 86.8 % (95 % CI 82.1-90.7%), and NPV = 57.5 % (95 % CI 50.8-64.0%). CONCLUSIONS: Claims-based definitions using groups of ICD-10-CM codes assigned by neurologists in routine outpatient clinic visits at a level 4 epilepsy center performed well in discriminating between patients with and without a diagnosis of epilepsy and between seizure types.

Implementing standardized provider documentation in a tertiary epilepsy clinic.

OBJECTIVE: To incorporate standardized documentation into an epilepsy clinic and to use these standardized data to compare patients' perception of epilepsy diagnosis to provider documentation. METHODS: Using quality improvement methodology, we implemented interventions to increase documentation of epilepsy diagnosis, seizure frequency, and type from 49.8% to 70% of adult nonemployee patients seen by 6 providers over 5 months of routine clinical care. The main intervention consisted of an interactive SmartPhrase that mirrored a documentation template developed by the Epilepsy Learning Healthcare System. We assessed the weekly proportion of complete SmartPhrases among eligible patient encounters with a statistical process control chart. We used a subset of patients with established epilepsy care linked to existing patient-reported survey data to examine the proportion of patient-to-provider agreement on epilepsy diagnosis (yes vs no/unsure). We also examined sociodemographic and clinical characteristics of patients who disagreed vs agreed with provider's documentation of epilepsy diagnosis. RESULTS: The median SmartPhrase weekly completion rate was 78%. Established patients disagreed with providers with respect to epilepsy diagnosis in 18.5% of encounters (κ = 0.13), indicating that they did not have or were unsure if they had epilepsy despite having a provider-documented epilepsy diagnosis. Patients who disagreed with providers were similar to those who agreed with respect to age, sex, ethnicity, marital status, seizure frequency, type, and other quality-of-life measures. CONCLUSION: This project supports the feasibility of implementing standardized documentation of data relevant to epilepsy care in a tertiary epilepsy clinic and highlights an opportunity for improvement in patient-provider communication.

A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation.

Alzheimer's disease (AD) is a multifaceted disease that is characterized by increased oxidative stress, metal-ion dysregulation, and the formation of intracellular neurofibrillary tangles and extracellular amyloid-ß (Aß) aggregates. In this work we report the large affinity binding of the iron(iii) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole complex FeL1 to the Aß peptide (K d ∼ 10-7) and the ability of the bound FeL1 to act as a catalytic antioxidant in both the presence and absence of Cu(ii) ions. Specific findings are that: (a) an Aß histidine residue binds axially to FeL1; (b) that the resulting adduct is an efficient catalase; (c) this interaction restricts the formation of high molecular weight peptide aggregates. UV-Vis and electron paramagnetic resonance (EPR) studies show that although the binding of FeL1 does not influence the Aß-Cu(ii) interaction (K d ∼ 10-10), bound FeL1 still acts as an antioxidant thereby significantly limiting reactive oxygen species (ROS) generation from Aß-Cu. Overall, FeL1 is shown to bind to the Aß peptide, and modulate peptide aggregation. In addition, FeL1 forms a ternary species with Aß-Cu(ii) and impedes ROS generation, thus showing the promise of discrete metal complexes to limit the toxicity pathways of the Aß peptide.

Medicare claims can identify post-stroke epilepsy.

OBJECTIVE: There have been no validated Medicare claims-based algorithms available to identify epilepsy by discrete etiology of stroke (e.g., post-stroke epilepsy, PSE) in community-dwelling elderly individuals, despite the increasing availability of large datasets. Our objective was to validate algorithms that detect which patients have true PSE. METHODS: We linked electronic health records (EHR) to Medicare claims from a Medicare Pioneer Accountable Care Organization (ACO) to identify PSE. A neurologist reviewed 01/2012-12/2014 EHR data from a stratified sample of Medicare patients aged 65+ years to adjudicate a reference-standard to develop an algorithm for identifying patients with PSE. Patient sampling strata included those with: A) epilepsy-related claims diagnosis (n = 534 [all]); B) no diagnosis but neurologist visit (n = 500 [randomly sampled from 4346]); C) all others (n = 500 [randomly sampled from 16,065]). We reconstructed the full sample using inverse probability sampling weights; then used half to derive algorithms and assess performance, and the remainder to confirm performance. We evaluated predictive performance across several measures, e.g., specificity, sensitivity, negative and positive predictive values (NPV, PPV). We selected our best performing algorithms based on the greatest specificity and sensitivity. RESULTS: Of 20,943 patients in the reconstructed sample, 13.6% of patients with epilepsy had reference-standard PSE diagnosis, which represents a 3-year overall prevalence of 0.28% or 28/10,000, and a prevalence within the subpopulation with stroke of 3%. The best algorithm included three conditions: (a) at least one cerebrovascular claim AND one epilepsy-specific anticonvulsant OR (b) at least one cerebrovascular claim AND one electroencephalography claim (specificity 100.0% [95% CI 99.9%-100.0%], NPV 98.8% [98.6%-99.0%], sensitivity 20.6% [95% CI 14.6%-27.9%], PPV 86.5% [95% CI 71.2%-95.5%]). CONCLUSION: Medicare claims can identify elderly Medicare beneficiaries with PSE with high accuracy. Future epidemiological surveillance of epilepsy could incorporate similar algorithms to accurately identify epilepsy by varying etiologies.

Epilepsy Among Elderly Medicare Beneficiaries: A Validated Approach to Identify Prevalent and Incident Epilepsy.

BACKGROUND: Uncertain validity of epilepsy diagnoses within health insurance claims and other large datasets have hindered efforts to study and monitor care at the population level. OBJECTIVES: To develop and validate prediction models using longitudinal Medicare administrative data to identify patients with actual epilepsy among those with the diagnosis. RESEARCH DESIGN, SUBJECTS, MEASURES: We used linked electronic health records and Medicare administrative data including claims to predict epilepsy status. A neurologist reviewed electronic health record data to assess epilepsy status in a stratified random sample of Medicare beneficiaries aged 65+ years between January 2012 and December 2014. We then reconstructed the full sample using inverse probability sampling weights. We developed prediction models using longitudinal Medicare data, then in a separate sample evaluated the predictive performance of each model, for example, area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity. RESULTS: Of 20,945 patients in the reconstructed sample, 2.1% had confirmed epilepsy. The best-performing prediction model to identify prevalent epilepsy required epilepsy diagnoses with multiple claims at least 60 days apart, and epilepsy-specific drug claims: AUROC=0.93 [95% confidence interval (CI), 0.90-0.96], and with an 80% diagnostic threshold, sensitivity=87.8% (95% CI, 80.4%-93.2%), specificity=98.4% (95% CI, 98.2%-98.5%). A similar model also performed well in predicting incident epilepsy (k=0.79; 95% CI, 0.66-0.92). CONCLUSIONS: Prediction models using longitudinal Medicare data perform well in predicting incident and prevalent epilepsy status accurately.

Modification of Aß Peptide Aggregation via Covalent Binding of a Series of Ru(III) Complexes.

Alzheimer's disease (AD) is the most common form of dementia, leading to loss of cognition, and eventually death. The disease is characterized by the formation of extracellular aggregates of the amyloid-beta (Aß) peptide and neurofibrillary tangles of tau protein inside cells, and oxidative stress. In this study, we investigate a series of Ru(III) complexes (Ru-N) derived from NAMI-A in which the imidazole ligand has been substituted for pyridine derivatives, as potential therapeutics for AD. The ability of the Ru-N series to bind to Aß was evaluated by NMR and ESI-MS, and their influence on the Aß peptide aggregation process was investigated via electrophoresis gel/western blot, TEM, turbidity, and Bradford assays. The complexes were shown to bind covalently to the Aß peptide, likely via a His residue. Upon binding, the complexes promote the formation of soluble high molecular weight aggregates, in comparison to peptide precipitation for peptide alone. In addition, TEM analysis supports both amorphous and fibrillar aggregate morphology for Ru-N treatments, while only large amorphous aggregates are observed for peptide alone. Overall, our results show that the Ru-N complexes modulate Aß peptide aggregation, however, the change in the size of the pyridine ligand does not substantially alter the Aß aggregation process.