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.

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.

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.

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.

Multifunctional Compounds for Activation of the p53-Y220C Mutant in Cancer.

The p53 protein plays a major role in cancer prevention, and over 50 % of cancer diagnoses can be attributed to p53 malfunction. The common p53 mutation Y220C causes local protein unfolding, aggregation, and can result in a loss of Zn in the DNA-binding domain. Structural analysis has shown that this mutant creates a surface site that can be stabilized using small molecules, and herein a multifunctional approach to restore function to p53-Y220C is reported. A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53-Y220C surface cavity, and Zn-binding fragments for metallochaperone activity. Their Zn-binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds L4 and L5 to increase intracellular levels of Zn2+ in a p53-Y220C-mutant cell line. The in vitro cytotoxicity of our compounds was initially screened by the National Cancer Institute (NCI-60), followed by testing in three stomach cancer cell lines with varying p53 status', including AGS (WTp53), MKN1 (V143A), and NUGC3 (Y220C). Our most promising ligand, L5, is nearly 3-fold more cytotoxic than cisplatin in a large number of cell lines. The impressive cytotoxicity of L5 is further maintained in a NUGC3 3D spheroid model. L5 also induces Y220C-specific apoptosis in a cleaved caspase-3 assay, reduces levels of unfolded mutant p53, and recovers p53 transcriptional function in the NUGC3 cell line. These results show that these multifunctional scaffolds have the potential to restore wild-type function in mutant p53-Y220C.

Ketimine reductase/CRYM catalyzes reductive alkylamination of α-keto acids, confirming its function as an imine reductase.

Recently, crystalized mouse ketimine reductase/CRYM complexed with NADPH was found to have pyruvate bound in its active site. We demonstrate that the enzyme binds α-keto acids, such as pyruvate, in solution, and catalyzes the formation of N-alkyl-amino acids from alkylamines and α-keto acids (via reduction of imine intermediates), but at concentrations of these compounds not expected to be encountered in vivo. These findings confirm that, mechanistically, ketimine reductase/CRYM acts as a classical imine reductase and may explain the finding of bound pyruvate in the crystallized protein.

Mutation of cysteine residues alters the heme-binding pocket of indoleamine 2,3-dioxygenase-1.

The hemoprotein indoleamine 2,3-dioxygenase-1 (IDO1) is the first and rate-limiting enzyme in mammalian tryptophan metabolism. Interest in IDO1 continues to grow, due to the ever expanding influence IDO1 plays in the immune response. This study examined the contribution of all individual cysteine residues towards the overall catalytic properties and stability of recombinant human IDO1 via mutagenesis studies using a range of biochemical and spectroscopic techniques, including in vitro kinetic assessment, secondary structure identification via circular dichroism spectroscopy and thermal stability assessment. Upon mutation of cysteine residues we observed changes in secondary structure (principally, shifting from α-helix/ß-sheet features to random coil structures) that produced out of plane heme torsion and puckering, changes to thermal stability (including gains in stability for one mutant protein) and differences in enzymatic activity (such as, increased ability to convert non-natural substrates, e.g.d-tryptophan) from wild type IDO1 enzyme.

Global transcriptional analysis of psoriatic skin and blood confirms known disease-associated pathways and highlights novel genomic "hot spots" for differentially expressed genes.

There are major gaps in our knowledge regarding the exact mechanisms and genetic basis of psoriasis. To investigate the pathogenesis of psoriasis, gene expression in 10 skin (5 lesional, 5 nonlesional) and 11 blood (6 psoriatic, 5 nonpsoriatic) samples were examined using Affymetrix HG-U95A microarrays. We detected 535 (425 upregulated, 110 downregulated) DEGs in lesional skin at 1% false discovery rate (FDR). Combining nine microarray studies comparing lesional and nonlesional psoriatic skin, 34.5% of dysregulated genes were overlapped in multiple studies. We further identified 20 skin and 2 blood associated transcriptional "hot spots" at specified genomic locations. At 5% FDR, 11.8% skin and 10.4% blood DEGs in our study mapped to one of the 12 PSORS loci. DEGs that overlap with PSORS loci may offer prioritized targets for downstream genetic fine mapping studies. Novel DEG "hot spots" may provide new targets for defining susceptibility loci in future studies.

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.

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.

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.

Novel indoleamine 2,3-dioxygenase-1 inhibitors from a multistep in silico screen.

Indoleamine 2,3-dioxygenase-1 (IDO-1) is a heme containing enzyme that catalyses the initial step in the major pathway of l-tryptophan catabolism; the kynurenine pathway. A large body of evidence has been accumulating for its immunosuppressive and tumoural escape roles and its applicability as a therapeutic target. Of particular interest is the possibility that IDO-1 inhibition may arrest, and sometimes revert, tumour growth. There exists a continuing need for the development of new and specific inhibitors for IDO-1, and we have created three pharmacophores designed to aid in this search. Initial database hits were further screened using Kier flexibility and a 'What-If' docking technique, designed to overcome the inherent limitations of today's forcefields with regards to heme chemistry. Eighteen compounds were tested in vitro, yielding four novel inhibitors with low micromolar IC(50) values, comparable with current inhibitors.

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.

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.

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.

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.

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.

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.