Functional and structural characterization of treatment-emergent nirmatrelvir resistance mutations at low frequencies in the main protease (Mpro) reveals a unique evolutionary route for SARS-CoV-2 to gain resistance.

Background: The main protease (Mpro) is one of the most attractive targets for antiviral drug discovery against SARS-CoV-2. Mutations in Mpro have been linked to resistance against nirmatrelvir-ritonavir (NIR-RIT), an important therapy for SARS-CoV-2 infection. This study aimed to identify low-frequency antiviral resistance mutations in Mpro from NIR-RIT-treated patients and to analyze the enzymatic properties, inhibitor susceptibility, and structural features of new Mpro clinical variants.

Contribution of Modifiable Midlife and Late-Life Vascular Risk Factors to Incident Dementia.

Importance: Midlife vascular risk factors are associated with an elevated risk of dementia. However, the total contribution of vascular risk factors in midlife and late life with incident dementia is uncertain.

Objective: To quantify the proportion of incident dementia attributable to modifiable vascular risk factors measured in midlife and late life and to examine differences by apolipoprotein ε4 genotype, self-reported race, and sex.

Population Attributable Fraction of Incident Dementia Associated With Hearing Loss.

Importance: Hearing loss treatment delays cognitive decline in high-risk older adults. The preventive potential of addressing hearing loss on incident dementia in a community-based population of older adults, and whether it varies by method of hearing loss measurement, is unknown.

Objective: To calculate the population attributable fraction of incident dementia associated with hearing loss in older adults and to investigate differences by age, sex, self-reported race, and method of hearing loss measurement.

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 (). Our lead direct-acting antiviral (DAA), , is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

Modification of Aβ 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 (Aβ) peptide and neurofibrillary tangles of tau protein inside cells, and oxidative stress. In this study, we investigate a series of Ru(III) complexes () derived from NAMI-A in which the imidazole ligand has been substituted for pyridine derivatives, as potential therapeutics for AD.

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-β (Aβ) 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 to the Aβ peptide ( ∼ 10) and the ability of the bound to act as a catalytic antioxidant in both the presence and absence of Cu(ii) ions. Specific findings are that: (a) an Aβ histidine residue binds axially to ; (b) that the resulting adduct is an efficient catalase; (c) this interaction restricts the formation of high molecular weight peptide aggregates.

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.