AC-ASPECTS, ACh-ASPECTS, and H-ASPECTS: new imaging scales to assess territorial and total cerebral hemispheric ischemic injury.

Background: The extent of ischemic injury in acute stroke is assessed in clinical practice using the Acute Stroke Prognosis Early CT Score (ASPECTS) rating system. However, current ASPECTS semi-quantitative topographic scales assess only the middle cerebral artery (MCA) (original ASPECTS) and posterior cerebral (PC-ASPECTS) territories. For treatment decision-making in patients with anterior cerebral artery (ACA) occlusions and internal carotid artery (ICA) occlusions with large ischemic cores, measures of all hemispheric regions are desirable. Methods: In this cohort study, anatomic rating systems were developed for the anterior cerebral (AC-ASPECTS, 3 points) and anterior choroidal artery (ACh-ASPECTS, 1 point) territories. In addition, a total supratentorial hemisphere (H-ASPECTS, 16 points) score was calculated as the sum of the MCA ASPECTS (10 regions), supratentorial PC-ASPECTS (2 regions), AC-ASPECTS (3 regions), and ACh-ASPECTS (1 region). Three raters applied these scales to initial and 24 h CT and MR images in consecutive patients with ischemic stroke (IS) due to ICA, M1-MCA, and ACA occlusions. Results: Imaging ratings were obtained for 96 scans in 50 consecutive patients with age 74.8 (±14.0), 60% female, NIHSS 15.5 (9.25-20), and occlusion locations ICA 34%; M1-MCA 58%; and ACA 8%. Treatments included endovascular thrombectomy +/- thrombolysis in 72%, thrombolysis alone in 8%, and hemicraniectomy in 4%. Among experienced clinicians, inter-rater reliability for AC-, ACh-, and H-ASPECTS scores was substantial (kappa values 0.61-0.80). AC-ASPECTS abnormality was present in 14% of patients, and ACh-ASPECTS abnormality in 2%. Among patients with ACA and ICA occlusions, H-ASPECTS scores compared with original ASPECTS scores were more strongly associated with disability level at discharge, ambulatory status at discharge, discharge destination, and combined inpatient mortality and hospice discharge. Conclusion: AC-ASPECTS, ACh-ASPECTS, and H-ASPECTS expand the scope of acute IS imaging scores and increase correlation with functional outcomes. This additional information may enhance prognostication and decision-making, including endovascular thrombectomy and hemicraniectomy.

Modified Rankin Scale Disability Status at Day 4 Poststroke is an Informative Predictor of Long-Term Day 90 Outcome.

Background: Long-term disability after stroke is standardly assessed 3 months post-onset, using the modified Rankin Scale (mRS). The value of an early, day 4 mRS assessment for projecting the 3-month disability outcome has not been formally investigated. Methods: In this cohort of patients with acute cerebral ischemia and intracranial hemorrhage, we analyzed day 4 and day 90 mRS assessments in the NIH Field Administration of Stroke Therapy- Magnesium (FAST-MAG) Phase 3 trial. The performance of day 4 mRS, alone and as part of multivariate models, in predicting day 90 mRS was assessed using correlation coefficients, percent agreement, and the kappa statistics. Results: Among the 1573 acute cerebrovascular disease (ACVD) patients, 1206 (76.7%) had acute cerebral ischemia (ACI), while 367 (23.3%) had intracranial hemorrhage. Among all 1573 ACVD patients, day 4 mRS and day 90 mRS correlated strongly, Spearman's rho=0.79, in unadjusted analysis with weighted kappa of 0.59. For dichotomized outcomes, simple carry-forward of the day 4 mRS performed fairly well in agreeing with day 90 mRS: mRS 0-1 (k=0.67), 85.4%; mRS 0-2 (k=0.59), 79.5%; fatal outcome, 88.3% (k=0.33). Correlations of 4d and 90d mRS were stronger for ACI than ICH patients, 0.76 vs 0.71. Conclusions: In this acute cerebrovascular disease patient cohort, assessment of global disability performed on day 4 is highly informative regarding long-term, 3-month mRS disability outcome, alone, and even more strongly in combination with baseline prognostic variables. The day 4 mRS is a useful measure for imputing the final patient disability outcome in clinical trials and quality improvement programs.

Essential information for neurorecovery clinical trial design: trajectory of global disability in first 90 days post-stroke in patients discharged to acute rehabilitation facilities.

BACKGROUND: Many stroke recovery interventions are most beneficial when started 2-14d post-stroke, a time when patients become eligible for inpatient rehabilitation facilities (IRF) and neuroplasticity is often at its peak. Clinical trials focused on recovery need to expand the time from this plasticity to later outcome timepoints. METHODS: The disability course of patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) enrolled in Field Administration of Stroke Therapy Magnesium (FAST-MAG) Trial with moderate-severe disability (modified Rankin Scale [mRS] 3-5) on post-stroke day4 who were discharged to IRF 2-14d post-stroke were analyzed. RESULTS: Among 1422 patients, 446 (31.4%) were discharged to IRFs, including 23.6% within 2-14d and 7.8% beyond 14d. Patients with mRS 3-5 on day4 discharged to IRFs between 2-14d accounted for 21.7% (226/1041) of AIS patients and 28.9% (110/381) of ICH patients, (p < 0.001). Among these AIS patients, age was 69.8 (± 12.7), initial NIHSS median 8 (IQR 4-12), and day4 mRS = 3 in 16.4%, mRS = 4 in 50.0%, and mRS = 5 in 33.6%. Among these ICH patients, age was 62.4 (± 11.7), initial NIHSS median 9 (IQR 5-13), day 4 mRS = 3 in 9.4%, mRS = 4 in 45.3%, and mRS = 5 in 45.3% (p < 0.01 for AIS vs ICH). Between day4 to day90, mRS improved ≥ 1 levels in 72.6% of AIS patients vs 77.3% of ICH patients, p = 0.3. For AIS, mRS improved from mean 4.17 (± 0.7) to 2.84 (± 1.5); for ICH, mRS improved from mean 4.35 (± 0.7) to 2.75 (± 1.3). Patients discharged to IRF beyond day14 had less improvement on day90 mRS compared with patients discharged between 2-14d. CONCLUSIONS: In this acute stroke cohort, nearly 1 in 4 patients with moderate-severe disability on post-stroke day4 were transferred to IRF within 2-14d post-stroke. ICH patients had nominally greater mean improvement on mRS day90 than AIS patients. This course delineation provides a roadmap for future rehabilitation intervention studies.

Morning SARS-CoV-2 testing yields better detection of infection due to higher viral loads in saliva and nasal swabs upon waking

BackgroundThe analytical sensitivities of SARS-CoV-2 diagnostic tests span 6 orders of magnitude. Optimizing sample-collection methods to achieve the most reliable detection for a given sensitivity would increase the effectiveness of testing and minimize COVID-19 outbreaks. MethodsFrom September 2020 to April 2021 we performed a household-transmission study in which participants self-collected samples every morning and evening throughout acute SARS-CoV-2 infection. Seventy mildly symptomatic participants collected saliva and, of those, 29 also collected nasal-swab samples. Viral load was quantified in 1194 saliva and 661 nasal-swab samples using a high-analytical-sensitivity RT-qPCR assay (LOD, 1,000 SARS-CoV-2 RNA copies/mL). FindingsViral loads in both saliva and nasal-swab samples were significantly higher in morning-collected samples than evening-collected samples after symptom onset. We used these quantitative measurements to infer which diagnostic tests would have detected infection (based on sample type and test analytical sensitivity). We find that morning collection would have resulted in significantly improved detection and that this advantage would be most pronounced for tests with low to moderate analytical sensitivity, which would likely have missed infections if sampling in the evening. InterpretationCollecting samples for COVID-19 testing in the morning offers a simple and low-cost improvement to clinical diagnostic sensitivity of low- to moderate-analytical-sensitivity tests. The phenomenon of higher viral loads in the morning may also have implications related to when transmission is more likely to occur. FundingBill & Melinda Gates Foundation, Ronald and Maxine Linde Center for New Initiatives (Caltech), Jacobs Institute for Molecular Engineering for Medicine (Caltech) RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSReliable COVID-19 diagnostic testing is critical to reducing transmission of SARS-CoV-2 and reducing cases of severe or fatal disease, particularly in areas with limited vaccine access or uptake. Saliva and anterior-nares nasal swabs are common sample types; however, different diagnostic tests using these sample types have a range of analytical sensitivities spanning 6 orders of magnitude, with limits of detection (LODs) between 102 and 108 genomic copy equivalents of SARS-CoV-2 RNA (copies) per mL of sample. Due to limitations in clinical laboratory capacity, many low-resource settings rely on COVID-19 tests that fall on the moderate (LODs of 104 to 105 copies/mL) to lower (LODs of 105 to 108 copies/mL) end of this spectrum of analytical sensitivity. Alterations in sample collection methods, including time of sample collection, may improve the performance of these diagnostics. Added value of this studyThis study quantifies viral loads from saliva and nasal-swab samples that were longitudinally self-collected by symptomatic patients in the morning immediately after waking and in the evening just prior to sleeping throughout the course of acute SARS-CoV-2 infection. The study cohort was composed of mildly or moderately symptomatic individuals (outpatients). This analysis demonstrates significantly higher viral loads in samples collected in the morning, relative to those collected in the evening. When using moderate to lower analytical sensitivity test methods, these loads are inferred to result in significantly better detection of infected individuals in the morning. Implications of available evidenceThese findings suggest that samples collected in the morning immediately after waking will better detect SARS-CoV-2 infection in symptomatic individuals tested by moderate to lower analytical sensitivity COVID-19 diagnostic tests (LODs at or above 104 viral copies per mL of sample), such as many rapid antigen tests currently available.

SARS-CoV-2 is detectable using sensitive RNA saliva testing days before viral load reaches detection range of low-sensitivity nasal swab tests

Early detection of SARS-CoV-2 infection is critical to reduce asymptomatic and pre-symptomatic transmission, curb the spread of variants by travelers, and maximize treatment efficacy. Low-sensitivity nasal-swab testing (antigen and some nucleic-acid-amplification tests) is commonly used for surveillance and symptomatic testing, but the ability of low-sensitivity nasal-swab tests to detect the earliest stages of infection has not been established. In this case-ascertained study, initially-SARS-CoV-2-negative household contacts of individuals diagnosed with COVID-19 prospectively self-collected paired anterior-nares nasal-swab and saliva samples twice daily for viral-load quantification by high-sensitivity RT-qPCR and digital-RT-PCR assays. We captured viral-load profiles from the incidence of infection for seven individuals and compared diagnostic sensitivities between respiratory sites. Among unvaccinated persons, high-sensitivity saliva testing detected infection up to 4.5 days before viral loads in nasal swabs reached the limit of detection of low-sensitivity nasal-swab tests. For most participants, nasal swabs reached higher peak viral loads than saliva, but were undetectable or at lower loads during the first few days of infection. High-sensitivity saliva testing was most reliable for earliest detection. Our study illustrates the value of acquiring early (within hours after a negative high-sensitivity test) viral-load profiles to guide the appropriate analytical sensitivity and respiratory site for detecting earliest infections. Such data are challenging to acquire but critical to design optimal testing strategies in the current pandemic and will be required for responding to future viral pandemics. As new variants and viruses emerge, up-to-date data on viral kinetics are necessary to adjust testing strategies for reliable early detection of infections.

SARS-CoV-2 Viral Load in Saliva Rises Gradually and to Moderate Levels in Some Humans

Transmission of SARS-CoV-2 in community settings often occurs before symptom onset, therefore testing strategies that can reliably detect people in the early phase of infection are urgently needed. Early detection of SARS-CoV-2 infection is especially critical to protect vulnerable populations who require frequent interactions with caretakers. Rapid COVID-19 tests have been proposed as an attractive strategy for surveillance, however a limitation of most rapid tests is their low sensitivity. Low-sensitivity tests are comparable to high sensitivity tests in detecting early infections when two assumptions are met: (1) viral load rises quickly (within hours) after infection and (2) viral load reaches and sustains high levels (>105- 106 RNA copies/mL). However, there are no human data testing these assumptions. In this study, we document a case of presymptomatic household transmission from a healthy young adult to a sibling and a parent. Participants prospectively provided twice-daily saliva samples. Samples were analyzed by RT-qPCR and RT-ddPCR and we measured the complete viral load profiles throughout the course of infection of the sibling and parent. This study provides evidence that in at least some human cases of SARS-CoV-2, viral load rises slowly (over days, not hours) and not to such high levels to be detectable reliably by any low-sensitivity test. Additional viral load profiles from different samples types across a broad demographic must be obtained to describe the early phase of infection and determine which testing strategies will be most effective for identifying SARS-CoV-2 infection before transmission can occur. One sentence summaryIn some human infections, SARS-CoV-2 viral load rises slowly (over days) and remains near the limit of detection of rapid, low-sensitivity tests.