Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

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Background and Purpose: In ischemic stroke, intravenous tenecteplase is noninferior to alteplase in selected patients and has some practical advantages. Several stroke centers in New Zealand changed to routine off-label intravenous tenecteplase due to improved early recanalization in large vessel occlusion, inconsistent access to thrombectomy within stroke networks, and for consistency in treatment protocols between patients with and without large vessel occlusion. We report the feasibility and safety outcomes in tenecteplase-treated patients. Methods: We performed a retrospective analysis of consecutive patients thrombolyzed with intravenous tenecteplase at 1 comprehensive and 2 regional stroke centers from July 14, 2018, to February 29, 2020. We report the baseline clinical characteristics, rates of symptomatic intracranial hemorrhage, and angioedema. These were then compared with patient outcomes with those treated with intravenous alteplase at 2 other comprehensive stroke centers. Multivariable mixed-effects logistic regression models were performed assessing the association of tenecteplase with symptomatic intracranial hemorrhage and independent outcome (modified Rankin Scale score, 0–2) at day 90. Results: There were 165 patients treated with tenecteplase and 254 with alteplase. Age (75 versus 74 years), sex (56% versus 60% male), National Institutes of Health Stroke Scale scores (8 versus 10), median door-to-needle times (47 versus 48 minutes), or onset-to-needle time (129 versus 130 minutes) were similar between the groups. Symptomatic intracranial hemorrhage occurred in 3 (1.8% [95% CI, 0.4–5.3]) tenecteplase patients compared with 7 (2.7% [95% CI, 1.1–5.7]) alteplase patients ( P =0.75). There were no differences between tenecteplase and alteplase in the rates of angioedema (4 [2.4%; 95% CI, 0.7–6.2] versus 1 [0.4%; 95% CI, 0.01–2.2], P =0.08) or 90-day functional independence (100 [61%] versus 140 [57%], P =0.47), respectively. In mixed-effects logistic regression models, there was no significant association between thrombolytic choice and symptomatic intracranial hemorrhage (odds ratio tenecteplase, 0.62 [95% CI, 0.14–2.80], P =0.53) or functional independence (odds ratio tenecteplase, 1.20 [95% CI, 0.74–1.95], P =0.46). Conclusions: Routine use of tenecteplase for stroke thrombolysis was feasible and had comparable safety profile and outcome to alteplase.

Social withdrawal, or refraining from social interaction in the presence of peers, places adolescents at risk of developing emotional problems like anxiety and depression. The personality traits of neuroticism and conscientiousness also relate to emotional difficulties. For example, high conscientiousness predicts lower incidence of anxiety disorders and depression, while high neuroticism relates to greater likelihood of these problems. Based on these associations, socially withdrawn adolescents high in conscientiousness or low in neuroticism were expected to have lower levels of anxiety and depressive symptoms. Participants included 103 adolescents (59% female) who reported on their personality traits in 8th grade and their anxiety and depressive symptoms in 9th grade. Peer ratings of social withdrawal were collected within schools in 8th grade. A structural equation model revealed that 8th grade withdrawal positively predicted 9th grade anxiety and depressive symptoms controlling for 8th grade anxiety and depressive symptoms, but neuroticism did not. Conscientiousness moderated the relation of withdrawal with depressive symptoms but not anxiety, such that high levels of conscientiousness attenuated the association between withdrawal and depressive symptoms. This buffering effect may stem from the conceptual relation between conscientiousness and self-regulation. Conscientiousness did not, however, moderate the association between withdrawal and anxiety, which may be partly due to the role anxiety plays in driving withdrawal. Thus, a conscientious, well-regulated personality partially protects withdrawn adolescents from the increased risk of emotional difficulties.

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The researchers examined differential outcomes related to two distinct motivations for withdrawal (preference for solitude and shyness) as well as the possibility that support from important others (mothers, fathers, and best friends) attenuate any such links. Adolescents (159 males, 171 females) reported on their motivations to withdraw, internalizing symptoms, and relationship quality in eighth grade, as well as their anxiety and depression in ninth grade. Using structural equation modeling, the authors found that maternal support weakened the association between shyness and internalizing problems; friend support weakened the association between preference for solitude and depression; and friend support strengthened the association between shyness and depression. Results suggest that shy adolescents may not derive the same benefits from supportive friendships as their typical peers.

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Behavioral inhibition (BI), a temperament trait characterized by fearful and wary responses to novelty, has been consistently identified as one of the primary precursors of the behavioral expression of anxious, socially reticent behavior with unfamiliar peers (Fox, Henderson, Marshall, Nichols, & Ghera, 2005). In turn, it has been proposed that the tendency to demonstrate fearful, wary behavior and refrain from interacting with unfamiliar peers may be a key antecedent to social withdrawal, the tendency to avoid social interaction when in the presence of familiar peers (Rubin, Coplan, & Bowker, 2009). Social withdrawal predicts a variety of negative social and emotional outcomes throughout childhood and adolescence. For instance, socially withdrawn children often experience peer rejection and exclusion (e.g. Gazelle & Spangler, 2007), perhaps because they are less socially competent and they demonstrate poor social-cognitive reasoning abilities relative to their non-withdrawn peers (e.g., Burgess, Wojslawowicz, Rubin, Rose-Krasnor, & Booth-LaForce, 2006; Stewart & Rubin, 1995). Perhaps as a result of these difficulties, socially withdrawn children come to perceive themselves as less socially competent and experience heightened loneliness, anxiety, and depressive symptoms relative to their non-withdrawn peers (e.g., Ladd, 2006; see Rubin et al., 2009 for a relevant transactional model of the developmental course of social withdrawal). As a result, it is essential to investigate factors that may disrupt the association between early BI and childhood social reticence in order to better understand