SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling.

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since its emergence in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation of double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, protein kinase R (PKR), and oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV infections including murine coronavirus and Middle East respiratory syndrome (MERS)-CoV. To determine how nsp15 functions during SARS-CoV-2 infection, we constructed a recombinant SARS-CoV-2 (nsp15mut) expressing catalytically inactivated nsp15, which we show promoted increased dsRNA accumulation. Infection with SARS-CoV-2 nsp15mut led to increased activation of the IFN signaling and PKR pathways in lung-derived epithelial cell lines and primary nasal epithelial air-liquid interface (ALI) cultures as well as significant attenuation of replication in ALI cultures compared to wild-type virus. This replication defect was rescued when IFN signaling was inhibited with the Janus activated kinase (JAK) inhibitor ruxolitinib. Finally, to assess nsp15 function in the context of minimal (MERS-CoV) or moderate (SARS-CoV-2) innate immune induction, we compared infections with SARS-CoV-2 nsp15mut and previously described MERS-CoV nsp15 mutants. Inactivation of nsp15 had a more dramatic impact on MERS-CoV replication than SARS-CoV-2 in both Calu3 cells and nasal ALI cultures suggesting that SARS-CoV-2 can better tolerate innate immune responses. Taken together, SARS-CoV-2 nsp15 is a potent inhibitor of dsRNA-induced innate immune response and its antagonism of IFN signaling is necessary for optimal viral replication in primary nasal ALI cultures.

Prognostic performance of the IABP-SHOCK II Risk Score among cardiogenic shock subtypes in the critical care cardiology trials network registry.

BACKGROUND: Risk stratification has potential to guide triage and decision-making in cardiogenic shock (CS). We assessed the prognostic performance of the IABP-SHOCK II score, derived in Europe for acute myocardial infarct-related CS (AMI-CS), in a contemporary North American cohort, including different CS phenotypes. METHODS: The critical care cardiology trials network (CCCTN) coordinated by the TIMI study group is a multicenter network of cardiac intensive care units (CICU). Participating centers annually contribute ≥2 months of consecutive medical CICU admissions. The IABP-SHOCK II risk score includes age > 73 years, prior stroke, admission glucose > 191 mg/dl, creatinine > 1.5 mg/dl, lactate > 5 mmol/l, and post-PCI TIMI flow grade < 3. We assessed the risk score across various CS etiologies. RESULTS: Of 17,852 medical CICU admissions 5,340 patients across 35 sites were admitted with CS. In patients with AMI-CS (n = 912), the IABP-SHOCK II score predicted a >3-fold gradient in in-hospital mortality (low risk = 26.5%, intermediate risk = 52.2%, high risk = 77.5%, P < .0001; c-statistic = 0.67; Hosmer-Lemeshow P = .79). The score showed a similar gradient of in-hospital mortality in patients with non-AMI-related CS (n = 2,517, P < .0001) and mixed shock (n = 923, P < .001), as well as in left ventricular (<0.0001), right ventricular (P = .0163) or biventricular (<0.0001) CS. The correlation between the IABP-SHOCK II score and SOFA was moderate (r2 = 0.17) and the IABP-SHOCK II score revealed a significant risk gradient within each SCAI stage. CONCLUSIONS: In an unselected international multicenter registry of patients admitted with CS, the IABP- SHOCK II score only moderately predicted in-hospital mortality in a broad population of CS regardless of etiology or irrespective of right, left, or bi-ventricular involvement.

A closer look at mammalian antiviral condensates.

Several biomolecular condensates assemble in mammalian cells in response to viral infection. The most studied of these are stress granules (SGs), which have been proposed to promote antiviral innate immune signaling pathways, including the RLR-MAVS, the protein kinase R (PKR), and the OAS-RNase L pathways. However, recent studies have demonstrated that SGs either negatively regulate or do not impact antiviral signaling. Instead, the SG-nucleating protein, G3BP1, may function to perturb viral RNA biology by condensing viral RNA into viral-aggregated RNA condensates, thus explaining why viruses often antagonize G3BP1 or hijack its RNA condensing function. However, a recently identified condensate, termed double-stranded RNA-induced foci, promotes the activation of the PKR and OAS-RNase L antiviral pathways. In addition, SG-like condensates known as an RNase L-induced bodies (RLBs) have been observed during many viral infections, including SARS-CoV-2 and several flaviviruses. RLBs may function in promoting decay of cellular and viral RNA, as well as promoting ribosome-associated signaling pathways. Herein, we review these recent advances in the field of antiviral biomolecular condensates, and we provide perspective on the role of canonical SGs and G3BP1 during the antiviral response.

Mechanisms and consequences of mRNA destabilization during viral infections.

During viral infection there is dynamic interplay between the virus and the host to regulate gene expression. In many cases, the host induces the expression of antiviral genes to combat infection, while the virus uses "host shut-off" systems to better compete for cellular resources and to limit the induction of the host antiviral response. Viral mechanisms for host shut-off involve targeting translation, altering host RNA processing, and/or inducing the degradation of host mRNAs. In this review, we discuss the diverse mechanisms viruses use to degrade host mRNAs. In addition, the widespread degradation of host mRNAs can have common consequences including the accumulation of RNA binding proteins in the nucleus, which leads to altered RNA processing, mRNA export, and changes to transcription.

Hospital variation of outcomes in status epilepticus.

OBJECTIVE: Understanding factors driving variation in status epilepticus outcomes would be critical to improve care. We evaluated the degree to which patient and hospital characteristics explained hospital-to-hospital variability in intubation and postacute outcomes. METHODS: This was a retrospective cohort study of Medicare beneficiaries admitted with status epilepticus between 2009 and 2019. Outcomes included intubation, discharge to a facility, and 30- and 90-day readmissions and mortality. Multilevel models calculated percent variation in each outcome due to hospital-to-hospital differences. RESULTS: We included 29 150 beneficiaries. The median age was 68 years (interquartile range [IQR] = 57-78), and 18 084 (62%) were eligible for Medicare due to disability. The median (IQR) percentages of each outcome across hospitals were: 30-day mortality 25% (0%-38%), any 30-day readmission 14% (0%-25%), 30-day status epilepticus readmission 0% (0%-3%), 30-day facility stay 40% (25%-53%), and intubation 46% (20%-61%). However, after accounting for many hospitals with small sample size, hospital-to-hospital differences accounted for 2%-6% of variation in all unadjusted outcomes, and approximately 1%-5% (maximally 8% for 30-day readmission for status epilepticus) after adjusting for patient, hospitalization, and/or hospital characteristics. Although many characteristics significantly predicted outcomes, the largest effect size was cardiac arrest predicting death (odds ratio = 10.1, 95% confidence interval = 8.8-11.7), whereas hospital characteristics (e.g., staffing, accreditation, volume, setting, services) all had lesser effects. SIGNIFICANCE: Hospital-to-hospital variation explained little variation in studied outcomes. Rather, certain patient characteristics (e.g., cardiac arrest) had greater effects. Interventions to improve outcomes after status epilepticus may be better focused on individual or prehospital factors, rather than at the inpatient systems level.

Validation of Vascular Location Subcodes for Acute Ischemic Stroke by the International Classification of Diseases-10.

BACKGROUND: Vascular region of infarct is part of the International Classification of Diseases-10 (ICD-10) coding scheme for ischemic stroke. These data could potentially be used for studies about vascular location, such as comparisons of anterior versus posterior circulation stroke. The objective of this study was to evaluate the validity of these subcodes. METHODS: We selected a random sample of 100 hospitalizations specifying 50 with anterior circulation ICD-10 ischemic stroke (carotid, anterior cerebral artery [CA], middle CA) and 50 with posterior circulation stroke (vertebral, basilar, cerebellar, posterior CA). The gold standard primary vascular distribution was scored using imaging studies and reports, blinded to the subcode. We compared gold-standard distribution to coded distribution and calculated the operating characteristics of ICD-10 posterior circulation versus anterior circulation codes with the gold standard. We also calculated the kappa statistic for agreement across all 7 vascular regions. RESULTS: In our population of 100 strokes, mean NIHSS was 8 (SD, 8). Head CT was performed in 95 % (95/100) and MRI in 77 % (77/100). The gold standard classified 55 primary posterior circulation strokes (26 PCA, 16 cerebellar, 8 basilar, 5 vertebral), 44 primary anterior circulation strokes (35 MCA, 6 carotid, 3 ACA), and 1 stroke with no infarct on imaging. The accuracy of the ICD-10 classification for primary posterior circulation stroke versus anterior circulation/no infarct was: sensitivity 89 % (49/55); specificity 98 % (44/45); positive predictive value 98 % (49/50); negative predictive value 88 % (44/50). The reliability of the 7-region classification was excellent (kappa 0.85). CONCLUSIONS: We found that ICD-10 classification of vascular location in routine practice correlates strongly with gold-standard localization for hospitalized ischemic stroke and supports validity in differentiating posterior versus anterior circulation. At a more granular vascular level, the location reliability was excellent, although limited data were available for some subcodes.

RNase L-induced bodies sequester subgenomic flavivirus RNAs and re-establish host RNA decay.

Subgenomic flavivirus RNAs (sfRNAs) are structured RNA elements encoded in the 3'-UTR of flaviviruses that promote viral infection by inhibiting cellular RNA decay machinery. Herein, we analyze the production of sfRNAs using single-molecule RNA fluorescence in situ hybridization (smRNA-FISH) and super-resolution microscopy during West Nile virus, Zika virus, or Dengue virus serotype 2 infection. We show that sfRNAs are initially localized diffusely in the cytosol or in processing bodies (P-bodies). However, upon activation of the host antiviral endoribonuclease, Ribonuclease L (RNase L), nearly all sfRNAs re-localize to antiviral biological condensates known as RNase L-induced bodies (RLBs). RLB-mediated sequestration of sfRNAs reduces sfRNA association with RNA decay machinery in P-bodies, which coincides with increased viral RNA decay. These findings establish a role of RLBs in promoting viral RNA decay, demonstrating the complex host-pathogen interactions at the level of RNA decay and biological condensation.

Condensation of RNase L promotes its rapid activation in response to viral infection in mammalian cells.

Oligoadenylate synthetase 3 (OAS3) and ribonuclease L (RNase L) are components of a pathway that combats viral infection in mammals. Upon detection of viral double-stranded RNA (dsRNA), OAS3 synthesizes 2'-5'-oligo(A), which activates the RNase domain of RNase L by promoting the homodimerization and oligomerization of RNase L monomers. Activated RNase L rapidly degrades all cellular mRNAs, shutting off several cellular processes. We sought to understand the molecular mechanisms underlying the rapid activation of RNase L in response to viral infection. Through superresolution microscopy and live-cell imaging, we showed that OAS3 and RNase L concentrated into higher-order cytoplasmic complexes known as dsRNA-induced foci (dRIF) in response to dsRNA or infection with dengue virus, Zika virus, or West Nile virus. The concentration of OAS3 and RNase L at dRIF corresponded with the activation of RNase L-mediated RNA decay. We showed that dimerized/oligomerized RNase L concentrated in a liquid-like shell surrounding a core OAS3-dRIF structure and dynamically exchanged with the cytosol. These data establish that the condensation of dsRNA, OAS3, and RNase L into dRIF is a molecular switch that promotes the rapid activation of RNase L upon detection of dsRNA in mammalian cells.

Geographic Variation of Prevalence of Alzheimer's Disease and Related Dementias in Central Appalachia.

Background: Alzheimer's disease and related dementias (ADRD) prevalence varies geographically in the United States. Objective: To assess whether the geographic variation of ADRD in Central Appalachia is explained by county-level sociodemographics or access to care. Methods: Centers for Medicare and Medicaid Services Public Use Files from 2015- 2018 were used to estimate county-level ADRD prevalence among all fee-for-service (FFS) beneficiaries with≥1 inpatient, skilled nursing facility, home health agency, hospital outpatient or Carrier claim with a valid ADRD ICD-9/10 code over three-years in Central Appalachia (Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia). Negative binomial regression was used to estimate prevalence overall, by Appalachian/non-Appalachian designation, and by rural/urban classification. Models were then adjusted for county-level: 1) FFS demographics (age, gender, and Medicaid eligibility), comorbidities; 2) population sociodemographics (race/ethnicity, education, aging population distribution, and renter-occupied housing); and 3) diagnostic access (PCP visits, neurology visits, and imaging scans). Results: Across the 591 counties in the Central Appalachian region, the average prevalence of ADRD from 2015- 2018 was 11.8%. ADRD prevalence was modestly higher for Appalachian counties both overall (PR: 1.03; 95% CI: 1.02, 1.04) and after adjustment (PR: 1.02; 95% CI: 1.00, 1.03) compared to non-Appalachian counties. This difference was similar among rural and urban counties (p = 0.326) but varied by state (p = 0.004). Conclusions: The relative variation in ADRD prevalence in the Appalachian region was smaller than hypothesized. The case mixture of the dual eligible population, accuracy of the outcome measurement, and impact of educational attainment in this region may contribute to this observation.

Billed advance care planning visits may be occurring among older adults with high risk of mortality.

CONTEXT: Advance care planning (ACP) is a process that helps people prepare to make decisions about their future medical care. OBJECTIVES: We sought to understand who was received billed ACP visits and measure the association with health care utilization, cost, and mortality. METHODS: We used a randomly sampled 20 % cohort of Medicare fee-for-service (FFS) beneficiaries' files to conduct a retrospective cohort study. Beneficiaries with a billed ACP visit were matched to controls using a 2-stage propensity score matching process that included assigning a pseudo-ACP visit date for controls. Outcomes included healthcare utilization, mortality, and total medical cost per month. We used descriptive statistics for univariate analysis and fit multilevel logistic regression, multilevel linear regression, or Cox regression models. RESULTS: We identified 183,513 beneficiaries who received any billed ACP visit and 550,539 matched controls. Of those who had a ACP visit, the mean age was 76.5 years and high-risk comorbidities were common: 16 % dementia, 10 % congestive heart failure, 10 % cancer. Beneficiaries who had an ACP visit had slightly more health care utilization than controls. Beneficiaries who had an ACP visit were more likely to die (3.1% vs. 1.0 %, p < 0.01, OR=3.0, 95 %CI 2.9-3.2) in the unadjusted and adjusted analyses compared to matched controls. Total monthly medical costs were 33 % higher among beneficiaries who had an ACP visit. CONCLUSION: Our results suggest that ACP visits may be preferentially utilized amongst individuals with higher risk of mortality. There may be an opportunity to increase ACP visits among older adults at lower risk for mortality. KEY MESSAGE: This article suggests that ACP visits are likely targeted to older adults with a higher risk of mortality than those at lower risk of mortality suggesting an opportunity to reach people before they are facing end-of-life decisions.

Estimating the Impact of Hospital-Level Variation on the Use of Inpatient Rehabilitation Facilities Versus Skilled Nursing Facilities on Individual Patients With Stroke.

BACKGROUND: There is substantial hospital-level variation in the use of Inpatient Rehabilitation Facilities (IRFs) versus Skilled Nursing Facilities (SNFs) among patients with stroke, which is poorly understood. Our objective was to quantify the net effect of the admitting hospital on the probability of receiving IRF or SNF care for individual patients with stroke. METHODS: Using Medicare claims data (2011-2013), a cohort of patients with acute stroke discharged to an IRF or SNF was identified. We generated 2 multivariable logistic regression models. Model 1 predicted IRF admission (versus SNF) using only patient-level factors, whereas model 2 added a hospital random effect term to quantify the hospital effect. The statistical significance and direction of the random effect terms were used to categorize hospitals as being either IRF-favoring, SNF-favoring, or neutral with respect to their discharge patterns. The hospital's impact on individual patient's probability of IRF discharge was estimated by taking the change in individual predicted probabilities (change in individual predicted probability) between the 2 models. Hospital-level effects were categorized as small (<10%), moderate (10%-19%), or large (≥20%) depending on change in individual predicted probability. RESULTS: The cohort included 135 415 patients (average age, 81.5 [SD=8.0] years, 61% female, 91% ischemic stroke) who were discharged from 1816 acute care hospitals to IRFs (n=66 548) or SNFs (n=68 867). Half of hospitals were classified as being either IRF-favoring (n=461, 25.4%) or SNF-favoring (n=485, 26.7%) with the remainder (n=870, 47.9%) considered neutral. Overall, just over half (n=73 428) of patients were treated at hospitals that had moderate or large independent effects on discharge settings. Hospital effects for neutral hospitals were small (ie, change in individual predicted probability <10%) for most patients (72.5%). However, hospital effects were moderate or large for 78.8% and 84.6% of patients treated at IRF- or SNF-favoring hospitals, respectively. CONCLUSIONS: For most patients with stroke, the admitting hospital meaningfully changed the type of rehabilitation care that they received.

G3BP1-dependent condensation of translationally inactive viral RNAs antagonizes infection.

G3BP1 is an RNA binding protein that condenses untranslating messenger RNAs into stress granules (SGs). G3BP1 is inactivated by multiple viruses and is thought to antagonize viral replication by SG-enhanced antiviral signaling. Here, we show that neither G3BP1 nor SGs generally alter the activation of innate immune pathways. Instead, we show that the RNAs encoded by West Nile virus, Zika virus, and severe acute respiratory syndrome coronavirus 2 are prone to G3BP1-dependent RNA condensation, which is enhanced by limiting translation initiation and correlates with the disruption of viral replication organelles and viral RNA replication. We show that these viruses counteract condensation of their RNA genomes by inhibiting the RNA condensing function of G3BP proteins, hijacking the RNA decondensing activity of eIF4A, and/or maintaining efficient translation. These findings argue that RNA condensation can function as an intrinsic antiviral mechanism, which explains why many viruses inactivate G3BP proteins and suggests that SGs may have arisen as a vestige of this antiviral mechanism.

Prescription Drug Prices: An AAN Position Statement.

This position statement serves to establish the AAN's stance on the methods to address the cost of prescription drugs being considered by state and federal policymakers so that the AAN can continue to advocate effectively for its members. Neurologists seek to provide high-value care for patients with neurologic diseases at the lowest cost possible. However, many therapies for neurologic diseases are among the most expensive in the United States. The 3 major cost challenges include (1) unjustified increases in the pricing for drugs used to treat neurologic disorders, (2) the high cost of medications used to treat rare diseases where there are limited or no therapeutic options available, and (3) the high cost of noninnovative (already FDA-approved) therapies that used accelerated FDA approval pathways or Orphan Drug Act designated to expedite approvals in neurologic disorders. In each of these cases, AAN is concerned that the high cost does not deliver sufficient value to patients or society. The AAN's position is that action must be taken to ensure that effective prescription medications are accessible for patients with complex, chronic neurologic conditions. Potential solutions should be affordable, simple, and transparent. Cost-containment efforts must also address the burden on the entire healthcare system because high prescription drug prices may be shifted and absorbed in ways that negatively affect patient and prescriber access to important medications. AAN supports price negotiations, the cost saving potential of generics and biosimilars, development of novel therapeutics, price transparency, and importation.

Are adverse events higher among patients with acute optic neuritis prescribed glucocorticoids? A retrospective, longitudinal cohort study.

OBJECTIVE: Optic neuritis (ON) is an acute focal inflammation of the optic nerve routinely treated with glucocorticoids. We aimed to compare adverse events (AE) among glucocorticoid-treated and untreated patients in the real world to guide clinical decision making about treatment tradeoffs. DESIGN: Retrospective, longitudinal cohort study. SETTING: Claims study from a large, private insurer in the USA (2005-2019). PARTICIPANTS: Adults≥18 years old with ≥1 ICD9/10 ON diagnosis with an evaluation/management visit code, and ≥6 months continuous enrolment prior to and following ON diagnosis. INTERVENTION: Glucocorticoid prescription exposure. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was any AE within 90 days of glucocorticoid prescription. Secondary outcome was AE assessment by severity. Generalised estimating equations with logit link assessed relationships between glucocorticoid prescription and AEs. High-dimensional propensity score analyses accounted for potential confounding (eg, sociodemographics and comorbidities). Sensitivity analyses restricted the cohort to high-dose prescriptions (≥100 mg prednisone equivalent, injection/infusion), AEs within 30 days, highly specific ON definition and traditional propensity score match. RESULTS: Of the 14 311 people with 17 404 ON claims, 66.3% were women (n=9481), predominantly White (78.2%; n=9940), with median age (IQR)=48 (37,60) years. Within 90 days of the claim, 15.7% (n=2733/17 404) were prescribed glucocorticoids. The median (IQR) prescription duration=10 (6,20) days. Any and severe AEs were higher among patients prescribed glucocorticoids versus none (any AEs: n=437/2733 (16.0%) vs n=1784/14 671 (12.2%), adjusted OR 1.33 (95% CI: 1.18 to 1.50); severe AEs: n=72/2733 (2.6%) vs n=273/14 671 (1.9%), adjusted OR 1.82 (95% CI: 1.37 to 2.35)). Sensitivity analyses were similar. CONCLUSIONS: Real-world glucocorticoid prescriptions among ON patients were short-term, associated with a 30% relative increase in potentially serious AEs captured within healthcare encounters, including those not previously observed, such as VTE. These results can inform treatment decisions, particularly for ON patients likely to experience only marginal benefits.

Premorbid Blood Pressure Control Modifies Risk of DWI Lesions With Acute Blood Pressure Reduction in Intracerebral Hemorrhage.

BACKGROUND: Hypoperfusion due to blood pressure (BP) reduction is a potential mechanism of cerebral ischemia after intracerebral hemorrhage. However, prior evaluations of the relationship between BP reduction and ischemia have been conflicting. Untreated chronic hypertension is common in intracerebral hemorrhage and alters cerebral autoregulation. We hypothesized that the risk of diffusion-weighted imaging (DWI) hyperintensities from acute BP reduction is modified by premorbid BP control. METHODS: Individuals enrolled in the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage) from 2010 to 2015 were categorized as untreated, treated, or nonhypertensive based on preintracerebral hemorrhage diagnosis and antihypertensive medication use. The percent reduction of systolic BP (SBP) was calculated between presentation and 24 hours from admission. The primary outcome was the presence of DWI lesions. Using logistic regression, we tested the association between chronic hypertension status, SBP reduction, and their interaction with DWI lesion presence. RESULTS: From 3000 participants, 877 with available magnetic resonance imaging met inclusion (mean age, 60.5±13.3 years; 42.5% women). DWI lesions were detected in 25.9%. Untreated, treated, and no hypertension accounted for 32.6%, 47.9%, and 19.5% of cases, respectively. SBP reduction was not directly associated with DWI lesions; however, an interaction effect was observed between SBP reduction and chronic hypertension status (P=0.036). Nonhypertensive subjects demonstrated a linear risk of DWI lesion presence with greater SBP reduction, whereas untreated hypertension demonstrated a stable risk across a wide range of SBP reduction (P=0.023). CONCLUSIONS: Premorbid BP control, especially untreated hypertension, may influence the relationship between DWI lesions and acute BP reduction after intracerebral hemorrhage. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01202864.

Beta amyloid PET scans for dementia diagnoses: Practice and research implications from CARE-IDEAS.

Beta amyloid PET scans are a minimally invasive biomarker that may inform Alzheimer's disease (AD) diagnosis. The Caregiver's Reactions and Experience (CARE) study, an IDEAS supplement, aimed to understand experiences of PET scan recipients and their care partners regarding motivations for scans, reporting and interpreting results, and impact of results. Patients with mild cognitive impairment or dementia who agreed to join the CARE-IDEAS study and their care partners participated in a baseline survey and follow-up survey approximately 18 months later, supplemented by in-depth qualitative interviews with subsets of participants. Patients who received scans and volunteered for follow-up research were more likely to be male, better educated, and have higher income than the general population. Survey information was merged with Medicare data. This article integrates findings from several CARE-IDEAS publications and provides implications for practice and research. Although most participants accurately reported scan results, they were often confused about their meaning for prognosis. Some participants reported distress with results, but there were no significant changes in measured depression, burden, or economic strain over time. Many respondents desired more information about prognosis and supportive resources. Scan results were not differentially associated with changes in service use over time. Findings suggest a need for carefully designed and tested tools for clinicians to discuss risks and benefits of scans and their results, and resources to support patients and care partners in subsequent planning. Learning of scan results provides a point-of-contact that should be leveraged to facilitate shared decision-making and person-centered longitudinal AD care.

PHOCUS: A Phase 3, Randomized, Open-Label Study of Sequential Treatment with Pexa-Vec (JX-594) and Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

Introduction: Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods: This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results: The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion: Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.

Association of Traditional and Nontraditional Risk Factors in the Development of Strokes Among Young Adults by Sex and Age Group: A Retrospective Case-Control Study.

BACKGROUND: Despite women having fewer traditional risk factors (eg, hypertension, diabetes), strokes are more common in women than men aged ≤45 years. This study examined the contributions of traditional and nontraditional risk factors (eg, migraine, thrombophilia) in the development of strokes among young adults. METHODS: This retrospective case-control study used Colorado's All Payer Claims Database (2012-2019). We identified index stroke events in young adults (aged 18-55 years), matched 1:3 to stroke-free controls, by (1) sex, (2) age±2 years, (3) insurance type, and (4) prestroke period. All traditional and nontraditional risk factors were identified from enrollment until a stroke or proxy-stroke date (defined as the prestroke period). Conditional logistic regression models stratified by sex and age group first assessed the association of stroke with counts of risk factors by type and then computed their individual and aggregated population attributable risks. RESULTS: We included 2618 cases (52% women; 73.3% ischemic strokes) and 7827 controls. Each additional traditional and nontraditional risk factors were associated with an increased risk of stroke in all sex and age groups. In adults aged 18 to 34 years, more strokes were associated with nontraditional (population attributable risk: 31.4% men and 42.7% women) than traditional risk factors (25.3% men and 33.3% women). The contribution of nontraditional risk factors declined with age (19.4% men and 27.9% women aged 45-55 years). The contribution of traditional risk factors peaked among patients aged 35 to 44 years (32.8% men and 39.7% women). Hypertension was the most important traditional risk factor and increased in contribution with age (population attributable risk: 27.8% men and 26.7% women aged 45 to 55 years). Migraine was the most important nontraditional risk factor and decreased in contribution with age (population attributable risk: 20.1% men and 34.5% women aged 18-35 years). CONCLUSIONS: Nontraditional risk factors were as important as traditional risk factors in the development of strokes for both young men and women and have a stronger association with the development of strokes in adults younger than 35 years of age.

Elevated Amyloid-ß PET Scan and Cognitive and Functional Decline in Mild Cognitive Impairment and Dementia of Uncertain Etiology.

BACKGROUND: Elevated amyloid-ß (Aß) on positron emission tomography (PET) scan is used to aid diagnosis of Alzheimer's disease (AD), but many prior studies have focused on patients with a typical AD phenotype such as amnestic mild cognitive impairment (MCI). Little is known about whether elevated Aß on PET scan predicts rate of cognitive and functional decline among those with MCI or dementia that is clinically less typical of early AD, thus leading to etiologic uncertainty. OBJECTIVE: We aimed to investigate whether elevated Aß on PET scan predicts cognitive and functional decline over an 18-month period in those with MCI or dementia of uncertain etiology. METHODS: In 1,028 individuals with MCI or dementia of uncertain etiology, we evaluated the association between elevated Aß on PET scan and change on a telephone cognitive status measure administered to the participant and change in everyday function as reported by their care partner. RESULTS: Individuals with either MCI or dementia and elevated Aß (66.6% of the sample) showed greater cognitive decline compared to those without elevated Aß on PET scan, whose cognition was relatively stable over 18 months. Those with either MCI or dementia and elevated Aß were also reported to have greater functional decline compared to those without elevated Aß, even though the latter group showed significant care partner-reported functional decline over time. CONCLUSIONS: Elevated Aß on PET scan can be helpful in predicting rates of both cognitive and functional decline, even among cognitively impaired individuals with atypical presentations of AD.