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Highlights d Protection from severe lung disease 1 year after mRNA-1273 vaccination in macaques d Protection in the lungs is coincident with a local anamnestic antibody response d Protection in upper airway is limited 1 year after mRNA-1273 vaccination d Neutralizing responses to Delta are low to undetectable 1 year after mRNA-1273 vaccination

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to antibody neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-specific vaccines would enhance immunity and protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing antibody titers against D614G were 4760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (pre-boost), respectively, and 320 and 110 for Omicron. Two weeks after boost, titers against D614G and Omicron increased to 5360 and 2980, respectively, for mRNA-1273 and 2670 and 1930 for mRNA-Omicron. Following either boost, 70-80% of spike-specific B cells were cross-reactive against both WA1 and Omicron. Significant and equivalent control of virus replication in lower airways was observed following either boost. Therefore, an Omicron boost may not provide greater immunity or protection compared to a boost with the current mRNA-1273 vaccine.

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BackgroundAlthough some risk factors for stroke readmission have been reported, the mortality risk is unclear. We sought to evaluate etiologies and predictors of 30-day readmissions and determine the associated mortality risk.MethodsThis is a retrospective case–control study evaluating 1,544 patients admitted for stroke (hemorrhagic, ischemic, or TIA) from January 2013 to December 2014. Of these, 134 patients readmitted within 30 days were identified as cases; 1,418 other patients, with no readmissions were identified as controls. Patients readmitted for hospice or elective surgery were excluded. An additional 248 patients deceased on index admission were included for only a comparison of mortality rates. Factors explored included socio-demographic characteristics, clinical comorbidities, stroke characteristics, and length of stay. Chi-square test of proportions and multivariable logistic regression were used to identify independent predictors of 30-day stroke readmissions. Mortality rates were compared for index admission and readmission and among readmission diagnoses.ResultsAmong the 1,544 patients in the main analysis, 67% of index stroke admissions were ischemic, 22% hemorrhagic, and 11% TIA. The 30-day readmission rate was 8.7%. The most common etiologies for readmission were infection (30%), recurrent stroke and TIA (20%), and cardiac complications (14%). Significantly higher proportion of those readmitted for recurrent strokes and TIAs presented within the first week (p = 0.039) and had a shorter index admission length of stay (p = 0.027). Risk factors for 30-day readmission included age >75 (p = 0.02), living in a facility prior to index stroke (p = 0.01), history of prior stroke (p = 0.03), diabetes (p = 0.03), chronic heart failure (p ≤ 0.001), atrial fibrillation (p = 0.03), index admission to non-neurology service (p < 0.01), and discharge to other than home (p < 0.01). On multivariate analysis, index admission to a non-neurology service was an independent predictor of 30-day readmission (p ≤ 0.01). The mortality after a within 30-day readmission after stroke was higher than index admission (36.6 vs. 13.8% p ≤ 0.001) (OR 3.6 95% CI 2.5–5.3). Among those readmitted, mortality was significantly higher for those admitted for a recurrent stroke (p = 0.006).ConclusionApproximately one-third of 30-day readmissions were infection related and one-fifth returned with recurrent stroke or TIA. Index admission to non-neurology service was an independent risk factor of 30-day readmissions. The mortality rate for 30-day readmission after stroke is more than 2.5 times greater than index admissions and highest among those readmitted for recurrent stroke. Identifying high-risk patients for readmission, ensuring appropriate level of service, and early outpatient follow-up may help reduce 30-day readmission and the high associated risk of mortality.

Expanding the arsenal of prophylactic approaches against SARS-CoV-2 is of utmost importance, specifically those strategies that are resistant to antigenic drift in Spike. Here, we conducted a screen with over 16,000 RNAi triggers against the SARS-CoV-2 genome using a massively parallel assay to identify hyper-potent siRNAs. We selected 10 candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity with IC50<20pM and strong neutralisation in live virus experiments. We further enhanced the activity by combinatorial pairing of the siRNA candidates to develop siRNA cocktails and found that these cocktails are active against multiple types of variants of concern (VOC). We examined over 2,000 possible mutations to the siRNA target sites using saturation mutagenesis and identified broad protection against future variants. Finally, we demonstrated that intranasal administration of the siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the Syrian hamster model. Our results pave the way to development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies.

mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. We immunized rhesus macaques at weeks 0 and 4 and assessed immune responses over one year in blood, upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody binding titers also decreased in bronchoalveolar lavage (BAL). Four days after challenge, virus was unculturable in BAL and subgenomic RNA declined ~3-log10 compared to control animals. In nasal swabs, sgRNA declined 1-log10 and virus remained culturable. Anamnestic antibody responses (590-fold increase) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost.

Bedtime noncompliance is one of the most common and treatable types of child sleep problems. Children who are noncompliant at bedtime are more likely to exhibit daytime somnolescence, which may in turn lead children to exhibit daytime misbehavior, impaired social functioning and poorer school achievement. In addition, these bedtime problems can have a number of negative consequences for members of the child's family, including parental sleep deprivation and depression. Behavioral parent-training approaches are considered the treatments of choice for bedtime noncompliance in young children. In this paper, we describe the evidence supporting a number of such approaches. We highlight several gaps in the treatment literature and we make recommendations for future research. Keywords: Bedtime Noncompliance, Parent Training, Sleep Problems Bedtime noncompliance in preschool and elementary-school school aged children is typically characterized by stalling, whining, or tantruming when bedtime approaches. Almost all children will exhibit these behaviors at some point in their young lives. Most parents have the skills to handle milder forms of bedtime noncompliance. However, when the intensity, duration, or frequency of these behaviors leads to disruptions in a family's functioning, mental health professionals can offer substantial help. These bedtime behaviors are best classified diagnostically as Behavioral Insomnia of Childhood, Limitsetting Type (2005 revision of the International Classification of Sleep Disorders; American Academy of Sleep Medicine). In this paper we will use the less awkward term "bedtime noncompliance" to describe this set of behaviors. Although some of the studies we will mention include infants, we will focus primarily on preschool and school aged children. For an excellent review of the entire class of sleep problems in children, including parasomnias, fears, and nightmare disorders see Sadeh (2005).There is evidence that bedtime noncompliance is one of the most common childhood behavior problems. While many surveys of sleep problems in children lump sleep problems together, a few studies have examined prevalence rates of bedtime noncompliance. Estimates vary widely, but most studies suggest that 5-10% of school-aged children display significant bedtime noncompliance (e.g. Blader, Koplewics, Abikoff, & Foley, 1997, Mindell, 1993. Sleep problems as a class account for almost 10% of presenting concerns in child and adolescent outpatient mental health centers (Meisbov, Schroeder, & Wesson, 1993). There is no doubt that many other families experience these problems and do not seek professional help. Research on Effects of Sleep ProblemsThere is an increasing amount of clinical observation and research demonstrating that sleep problems, including bedtime noncompliance, can lead to insufficient sleep in children, which can, if chronic, lead to emotional, physical, behavioral, and cognitive problems (Dahl, 1996; Gais, Philal, Wagner, & Born, 2000;Kuhn, Mayfield & Kuhn, 1999;Lavigne, et al., 199...