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There is an abundance of research that reveals our society’s stereotyping of older adults and the negative cultural images of the process of ageing (DeMuth, 2004; Fealy et al., 2012). These stereotypes–disinformations–that are attached to older individuals suggest that as we age, we enter a stage of stagnation, decline, and decreased resilience. However, there is substantial evidence that as people age, they still maintain considerable adaptability, mental resilience, and overall well being (Friedan, 1993, as cited in DeMuth, 2004). Rise, Shine, Sing! is a weekly online research-creation program that investigates how music, dance, and theatre can affect and contribute to the resilience and wellbeing of older adults. Through our work as research assistants on this project, we have observed the leaps and limitations of music theatre participants within our research community. Drawing from our experiences with the program, and reflecting upon our positionality in our research contexts, we will explore the ways in which misinformation and disinformation affect older individuals and the limitations placed on them by both society and themselves. Specifically, we will confront the stereotypes associated with older adulthood, the ageism present in the theatre industry, and resilience through the ageing process. At the same time, we will examine the ways that intergenerational communities, the importance of pursuing new passions, and creating opportunities to be expressive can enhance the lives and PERMA wellbeing of older adults. Our collective research and work with Rise, Shine, Sing! suggests that older adulthood can be a time of vibrancy, creativity, and increased agency.

Background: Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented. Methods: Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome. Results: There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94–93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95–93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82–65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79–67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75–84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54–0.70]) and correlated with lower mortality in patients P =0.022; unadjusted P =0.003). Median endogenous thrombin potential was within the normal range by the end of andexanet alfa bolus through 24 hours for all FXa inhibitors. Conclusions: In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02329327.

The article is devoted to the content of the theory of cosmism and its conceptual and methodological foundations. The analysis of the content of the works of foreign cosmists and their role in the world, philosophical, cultural and pedagogical science is given. The evolution of mankind has faced many crisis phenomena and negative consequences of their existence. Their impact on the world should be studied not only on the scale of the planet, but also in outer space. The balance between the negative and positive vector of the existence and development of our humanity remains quite fragile, which makes it inevitable to turn to the basic concept of "cosmism". This study reveals the content of the above concept, including the concept of "Russian cosmism", characteristics of the cosmic worldview. The main difference between foreign cosmism and Russian is shown. The concept of "human transformation" in the context of the philosophical and pedagogical direction, the concept of space pedagogy (pedagogy of cosmism, cosmopedagogy), methodological principles of the anthropocosmic concept of education are analyzed in their connection with the modern education system. An important methodological advantage of the pedagogy of cosmism is the consistency of the tasks set, the methodological educational principles included in it. The key and most promising methodological principles of cosmism for the modern education system are identified, which are reflected in cosmopedagogy and are its obvious advantages. The development of the child's cosmic self-consciousness, corresponding to feeling and intuition, must be taken into account in the content of modern education.

OBJECTIVES: Oral bacterial adhesion on dental implant materials has been extensively studied but has yielded results restricted to in vitro systems due to limitations in species selection, sustained fastidious anaerobe growth, and mixed culture longevity. The aim of this study was to develop an oral bacterial biofilm model consisting of colonizers representative of the oral microbiome exhibiting temporal shifts characteristic of plaque development and maturation in vivo. METHODS: Streptococcus oralis, Actinomyces naeslundii, Aggregatibacter actinomycetemcomitans, Veillonella parvula, Fusobacterium nucleatum, and Porphyromonas gingivalis were grown in monoculture prior to combination in mixed culture. Commercially pure titanium (cpTi) and yttria-stabilized zirconia (ZrO(2)) disks with polished, acid-etched, or sandblasted surfaces were prepared to evaluate oral bacterial adhesion. After 6 h, 1, 3, 7, 14 and 21 days, genomic DNA from planktonic and adherent bacteria was isolated. Quantitative polymerase chain reaction (PCR) was used to enumerate the amount and proportion of each species. RESULTS: Early colonizers S. oralis and A. actinomycetemcomitans, dominated after 6 h prior to secondary colonization by F. nucleatum and V. parvula in planktonic (1 day) and sessile (3 days) form. A. naeslundii maintained relatively low but stable bacterial counts throughout testing. After 14 days, P. gingivalis became established in mixed culture and persisted, becoming the dominant species after 21 days. The composition of adherent bacteria across all substrates was statistically similar at all timepoints with notable exceptions including lower S. oralis bacterial counts on polished cpTi (3 days). SIGNIFICANCE: Within the present model’s limitations, multispecies oral bacterial attachment is similar on surface-treated cpTi and ZrO(2).

Policing research and use of force policies have been guided by the continuum model for the past several decades. The continuum specifies a relationship between the amount of resistance a suspect presents and the amount of force that an officer should use to respond to or overcome a given level of resistance. In this paper, we show that resistance alone is an insufficient indicator of the necessity and level of force to be used both conceptually and empirically. We argue for the inclusion of considerations of perceived threat in the analysis of use of force incidents—both in policy and in research. Our analysis also reiterates the importance of police culture in understanding use of force decisions.

Background: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. Methods: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. Findings: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. Interpretation: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). Funding: KalVista Pharmaceuticals.

Mental health policies and plans (MHPPs) are important policy instruments and powerful tools to facilitate development of mental health systems and services across the world. We aimed to map and analyse methods and tools used to assess the extent, process and impact of implementing MHPPs. We systematically searched peer-reviewed and grey literature across seven scientific databases. We extracted and analysed the data on a) the characteristics of included studies (e.g., policy areas, region of origin, income setting) and b) the methodology and evaluation tools applied to assess the extent and process of implementation. We included 48 studies in the analyses. Twenty-six of these studies employed only qualitative methods (e.g., semi-structured interviews, focus group discussions, desk review, stakeholder consultations); 12 studies used quantitative methods (e.g., trend analysis, survey) and 10 used mixed-methods approaches. Generally, methods and tools used for assessment were described poorly with less than half of the studies providing partial or full details about them. Only three studies provided assessment of full policies. There is a lack of rigorous research to assess implementation MHPPs. Assessments of the implementation of entire MHPPs are almost non-existent. Strategies to assess the implementation of MHPPs should be an integral part of MHPPs.

Academic research aimed at measuring changes in officer behaviour typically focuses on agencies’ implementation of new training or modifications to policy. However, programmes to change officer behaviour are more likely to be successful when changes in policies are coupled with effective training. This paper reviews the importance of coupling training and policy changes to maximize the chances of modifying an officer’s behaviour. As an example, we present results from a quasi-experimental evaluation of a training programme paired with a policy modification regarding the application of an electronic control weapon (ECW). The evaluation used videos of a use-of-force encounter integrated into a pre- and post-survey asking officers for their recommended levels of force in the encounter. Results demonstrate that officers evaluated the circumstance differently after completing the training component and were less likely to recommend the use of the ECW.