saRNA vaccine expressing membrane-anchored RBD elicits broad and durable immunity against SARS-CoV-2 variants of concern.

Several vaccines have been widely used to counteract the global pandemic caused by SARS-CoV-2. However, due to the rapid emergence of SARS-CoV-2 variants of concern (VOCs), further development of vaccines that confer broad and longer-lasting protection against emerging VOCs are needed. Here, we report the immunological characteristics of a self-amplifying RNA (saRNA) vaccine expressing the SARS-CoV-2 Spike (S) receptor binding domain (RBD), which is membrane-anchored by fusing with an N-terminal signal sequence and a C-terminal transmembrane domain (RBD-TM). Immunization with saRNA RBD-TM delivered in lipid nanoparticles (LNP) efficiently induces T-cell and B-cell responses in non-human primates (NHPs). In addition, immunized hamsters and NHPs are protected against SARS-CoV-2 challenge. Importantly, RBD-specific antibodies against VOCs are maintained for at least 12 months in NHPs. These findings suggest that this saRNA platform expressing RBD-TM will be a useful vaccine candidate inducing durable immunity against emerging SARS-CoV-2 strains.

Psychotherapists' experience of the transition to telepsychotherapy amidst COVID-19 in India

Since the onset of COVID-19, the provision of psychotherapy services has shifted online. Thus, telepsychotherapy has been the focus of much research to document therapists' experiences;however, it has been mainly quantitative. In the Indian context, no known empirical research has focused on the implications of this transition on psychotherapists. Therefore, the present paper presents an in-depth idiographic study exploring psychotherapists' experiences in India, who had to transition to telepsychotherapy rapidly. Ten novice psychotherapists providing clinical services virtually were individually interviewed. The transcripts were analysed using interpretative phenomenological analysis. The main themes that emerged from the analysis were: negative impact on therapeutic process, detrimental effect on personal and professional self, positive impact of telepsychotherapy for therapist and, strategies for helping the adjustment to telepsychotherapy practice. The idiographic and psychological focus enabled a detailed exploration of the profound impact the sudden transition had on novice psychotherapists' work with clients and their self-efficacy. Despite contextual constraints faced by the psychotherapy profession in India, the participants demonstrated creative ways of working around the challenges encountered during telepsychotherapy. Nonetheless, their experiences highlight the need to initiate training programs in telepsychotherapy.

Best and Brightest? The Impact of Student Visa Restrictiveness on Who Attends College in the US

Before the COVID-19 pandemic, student F-1 visa applicants faced a 27 percent refusal rate that varies by time and region. Recent immigration policies have created uncertainty in whether international students will receive their visas. Using data on the universe of SAT takers between 2004 and 2015 matched with college enrollment records, we examine how the anticipated F-1 visa restrictiveness influences the enrollment of international students in the US. Using an instrumental variables approach, we find that a higher anticipated F-1 student visa refusal rate decreases the number of international SAT takers, decreases the probability of sending SAT scores to US colleges, and decreases international student enrollment in the US. The decreases are larger among international students with higher measured academic achievement. We also document academic achievement of international students and show that over 40 percent of high-scoring international SAT takers do not pursue US college education.

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial): A Multicentre, Randomised, Controlled Trial.

RATIONALE: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS). OBJECTIVES: We investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS. METHODS: This multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148). MEASUREMENTS: The primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit and hospital stays, and mortality were collected. Long-term follow up included diagnosis of interstitial lung disease at 1 year, and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at day 0, 4 and 7. MAIN RESULTS: 60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. CONCLUSION: ORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Isolation and quarantine for COVID-19 in the United States, 2020-2022.

BACKGROUND: Public health programs varied in ability to reach people with COVID-19 and their contacts to encourage separation from others. For both adult cases of COVID-19 and contacts, we estimated the impact of contact tracing activities on separation behaviors from January, 2020 until March, 2022. METHODS: We used a probability-based panel survey of a nationally representative sample to gather data for estimates and comparisons. RESULTS: An estimated 64,255,351 adults reported a positive SARS-CoV-2 test result; 79.6% isolated for >5 days, 60.2% isolated for >10 days, and 79.2% self-notified contacts. 24,057,139 (37.7%) completed a case investigation and 46.2% reported contacts to health officials. More adults who completed a case investigation isolated than adults who did not (>5 days, 82.6%; >10 days, 69.8% versus >5 days, 78.2% and >10 days 54.8%; p-values for both measures <0.05).84,946,636 adults were a contact to a COVID-19 case; 73.1% learned of their exposure directly from a case; 49.4% quarantined for >5 days, 18.7% quarantined for >14 days, and 13.5% completed a contact tracing call. More who completed a contact tracing call quarantined than those who did not (>5 days, 61.2%; >14 days, 25.2% versus >5 days, 48.5%; >14 days, 18.0%; p-values for both measures <0.05). CONCLUSIONS: Engagement in contact tracing positively correlated with isolation and quarantine. However, most adults with COVID-19 isolated and self-notified contacts regardless of whether the public health workforce was able to reach them. Identifying and reaching contacts was challenging, and limited the ability to promote quarantining, and testing.

Quantifying Mycobacterium tuberculosis transmission dynamics across global settings: a systematic analysis.

The degree to which individual heterogeneity in the production of secondary cases ("superspreading") affects tuberculosis (TB) transmission has not been systematically studied. We searched for population-based or surveillance studies in which whole genome sequencing was used to estimate TB transmission and the size distributions of putative TB transmission clusters were enumerated. We fit cluster size distribution data to a negative binomial branching process model to jointly infer the transmission parameters $R$ (the reproductive number) and dispersion parameter, $k$, which quantifies the propensity of superspreading in a population (generally, lower values of $k$ ($<1.0$) suggest increased heterogeneity). Of 4,796 citations identified in our initial search, nine studies met inclusion criteria ($n=5$ all TB; $n=4$ drug resistant TB) from eight global settings. Estimated $R$ values (range: 0.10, 0.73) were below 1.0, consistent with declining epidemics in the included settings; estimated $k$ values were well below 1.0 (range: 0.02, 0.48), indicating the presence of substantial individual-level heterogeneity in transmission across all settings. We estimated that a minority of cases (range 2-31%) drive the majority (80%) of ongoing transmission at the population level. Identifying sources of heterogeneity and accounting for them in TB control may have a considerable impact on mitigating TB transmission.

Family involvement, patient safety and suicide prevention in mental healthcare: ethnographic study.

BACKGROUND: Family involvement has been identified as a key aspect of clinical practice that may help to prevent suicide. AIMS: To investigate how families can be effectively involved in supporting a patient accessing crisis mental health services. METHOD: A multi-site ethnographic investigation was undertaken with two crisis resolution home treatment teams in England. Data included 27 observations of clinical practice and interviews with 6 patients, 4 family members, and 13 healthcare professionals. Data were analysed using framework analysis. RESULTS: Three overarching themes described how families and carers are involved in mental healthcare. Families played a key role in keeping patients safe by reducing access to means of self-harm. They also provided useful contextual information to healthcare professionals delivering the service. However, delivering a home-based service can be challenging in the absence of a supportive family environment or because of practical problems such as the lack of suitable private spaces within the home. At an organisational level, service design and delivery can be adjusted to promote family involvement. CONCLUSIONS: Findings from this study indicate that better communication and dissemination of safety and care plans, shared learning, signposting to carer groups and support for carers may facilitate better family involvement. Organisationally, offering flexible appointment times and alternative spaces for appointments may help improve services for patients.

Retaining Patients with Drug-Resistant Tuberculosis on Treatment During the COVID-19 Pandemic - Dharavi, Mumbai, India, 2020-2022.

Mumbai, India's second largest city, has one of the highest prevalences of drug-resistant tuberculosis* (DRTB) in the world. Treatment for DRTB takes longer and is more complicated than treatment for drug-susceptible tuberculosis (TB). Approximately 300 persons receive a new DRTB diagnosis each year in Mumbai's Dharavi slum†; historically, fewer than one half of these patients complete DRTB treatment. As nationwide restrictions to mitigate the COVID-19 pandemic were implemented, a program to facilitate uninterrupted DRTB care for patients receiving treatment was also implemented. A comprehensive tool and risk assessment provided support to DRTB patients and linked those who relocated outside of Dharavi during the pandemic to DRTB care at their destination. During May 2020-September 2022, a total of 973 persons received DRTB treatment in Dharavi, including 255 (26%) who relocated during treatment. Overall, 25 (3%) DRTB patients were lost to follow-up, a rate substantially lower than the rate before the pandemic (18%). Proactive planning and implementation of simple tools retained patients on treatment during periods of travel restrictions and relocations, improving programmatic outcomes. This approach might aid public health programs serving migrant populations or patients receiving treatment for DRTB during public health emergencies.

Clinical trials of self-replicating RNA-based cancer vaccines.

Therapeutic cancer vaccines, designed to activate immune effectors against tumor antigens, utilize a number of different platforms for antigen delivery. Among these are messenger RNAs (mRNA), successfully deployed in some prophylactic SARS-CoV2 vaccines. To enhance the immunogenicity of mRNA-delivered epitopes, self-replicating RNAs (srRNA) that markedly increase epitope expression have been developed. These vectors are derived from positive-strand RNA viruses in which the structural protein genes have been replaced with heterologous genes of interest, and the structural proteins are provided in trans to create single cycle viral replicon particles (VRPs). Clinical stage srRNA vectors have been derived from alphaviruses, including Venezuelan Equine Encephalitis (VEE), Sindbis, and Semliki Forest virus (SFV) and have encoded the tumor antigens carcinoembryonic antigen (CEA), human epidermal growth factor receptor 2 (HER2), prostate specific membrane antigen (PSMA), and human papilloma virus (HPV) antigens E6 and E7. Adverse events have mainly been grade 1 toxicities and minimal injection site reactions. We review here the clinical experience with these vaccines and our recent safety data from a study combining a VRP encoding HER2 plus an anti-PD1 monoclonal antibody (pembrolizumab). This experience with VRP-based srRNA supports recent development of fully synthetic srRNA technologies, where the viral structural proteins are replaced with protective lipid nanoparticles (LNP), cationic nanoemulsions or polymers.

The effects of the COVID-19 pandemic on French-Canadian adolescents' academic motivation: A follow-up study.

We previously shared results suggesting that the academic motivation of a sample of French-Canadian adolescents remained stable from few weeks before the first wave to the second wave of the COVID-19 pandemic. We here examine if this pattern persisted using data collected at a third time point.

COVID-19-related anxiety and trauma symptoms predict decreases in body image satisfaction in children.

The present study investigated short-term longitudinal effects of COVID-19-related trauma and separation, social, and generalized anxiety symptoms on children's body image satisfaction. Participants were 247 Canadian children (121 boys, 123 girls) aged between 7 and 12 years (M = 9.04). Two cohorts of parents were recruited to complete a questionnaire at two time points on their children's body image satisfaction and COVID-19-related trauma and anxiety symptoms. The first cohort (n = 136 children) was recruited in Summer 2020 and the second cohort (n = 111 children) was recruited in Winter 2021. For each cohort, follow-up surveys were completed approximately five months later, therefore covering an entire year with both cohorts. Multilevel regression analyses showed that children's trauma and anxiety at Time 1 predicted significant decreases in body image satisfaction at Time 2. Older children were especially at risk of decreased body image satisfaction as a result of their COVID-19-related trauma, social anxiety and generalized anxiety symptoms. Younger girls were susceptible to decreased body image satisfaction as a result of their separation anxiety symptoms. Given that children's body image dissatisfaction is a precursor to the development of eating disorders, these findings shed light on potential targets for early intervention with children who are at-risk of developing such difficulties.

The Impact of the COVID-19 Pandemic on the Anxiety of Adolescents in Québec.

Background: Several studies conducted since the beginning of the COVID-19 pandemic have shown its harmful effects on young people's mental health. In Québec and Canada, few studies have focussed on adolescents, and even fewer of these studies have examined this subject using a methodology that involved comparisons of data obtained before and during the pandemic, which is the purpose of this study. Objective: The objective of this study is to determine the impact of the COVID-19 pandemic on the anxiety of secondary 1 and 2 students in Québec, using data obtained before and during the pandemic. Method: Participants were 2990 French Canadian students in secondary 1 (grade 7) and secondary 2 (grade 8) in Québec. Two independent samples completed the questionnaires, one sample before the pandemic (fall 2019) and one sample during the pandemic (fall 2020). Their answers were subjected to descriptive analysis and multivariate analysis of variance. Results: Results show that the pandemic has had variable impacts on the student's mental health, with some of them reporting negative effects on their lives, others reporting no effect, and some reporting positive effect. However, the students surveyed during the pandemic generally reported more symptoms of generalized anxiety, and higher levels of test anxiety, fear of judgment and perfectionism than the ones surveyed before the pandemic. Conclusions: The discussion puts forward possible explanations for the results obtained, which contribute to a better understanding of young adolescents' experience during the COVID-19 pandemic. It also discusses the importance of developing interventions for adolescents affected by this pandemic.

A randomized, controlled, feasibility study of RD-X19 in subjects with mild-to-moderate COVID-19 in the outpatient setting.

The RD-X19 is an investigational, handheld medical device precisely engineered to emit blue light through the oral cavity to target the oropharynx and surrounding tissues. At doses shown to be noncytotoxic in an in vitro three-dimensional human epithelial tissue model, the monochromatic visible light delivered by RD-X19 results in light-initiated expression of immune stimulating cytokines IL-1α and IL-1ß, with corresponding inhibition of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) replication. A single exposure of 425 nm blue light at 60 J/cm2 led to greater than 99% reductions against all SARS-CoV-2 strains tested in vitro, including the more transmissible (Alpha) and immune evasive (Beta) variants. These preclinical findings along with other studies led to a randomized, double-blind, sham-controlled early feasibility study using the investigational device as a treatment for outpatients with mild to moderate coronavirus disease 2019 (COVID-19). The study enrolled 31 subjects with a positive SARS-CoV-2 antigen test and at least two moderate COVID-19 signs and symptoms at baseline. Subjects were randomized 2:1 (RD-X19: sham) and treated twice daily for 4 days. Efficacy outcome measures included assessments of SARS-CoV-2 saliva viral load and clinical assessments of COVID-19. There were no local application site reactions and no device-related adverse events. At the end of the study (day 8), the mean change in log10 viral load was -3.29 for RD-X19 and -1.81 for sham, demonstrating a treatment benefit of -1.48 logs (95% confidence internal, -2.88 to -0.071, nominal p = 0.040). Among the clinical outcome measures, differences between RD-X19 and sham were also observed, with a 57-h reduction of median time to sustained resolution of COVID-19 signs and symptoms (log rank test, nominal p = 0.044).

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial.

Importance: In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. Objective: To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. Design, Setting, and Participants: This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Interventions: Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). Main Outcomes and Measures: The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Results: Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Conclusions and Relevance: Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT02654327.

Other Primary Headache Disorders.

PURPOSE: This article provides an overview of a diverse group of primary headache disorders that are categorized in the International Classification of Headache Disorders, 3rd Edition (ICHD-3), as "other primary headache disorders." This article provides clinicians with a distilled understanding of the diagnoses and their epidemiology, pathophysiology, and management. RECENT FINDINGS: Cough-induced headache requires neuroimaging to exclude posterior fossa pathology and recently has been reported as a common symptom in patients with CSF-venous fistula. Clinical overlap is observed between patients with primary exercise headache and primary headache associated with sexual activity. Patients with recurrent thunderclap headache associated with sexual activity should be presumed to have reversible cerebral vasoconstriction syndrome until proven otherwise. De novo external-pressure headache is a common sequela among health care workers using personal protective equipment during the COVID-19 pandemic. New daily persistent headache is an important mimicker of chronic migraine or chronic tension-type headache and is distinguished by a daily-from-onset progression of persistent headache; a treatment-refractory course is often observed, and early involvement of a multidisciplinary team, including a psychotherapist, is advised. SUMMARY: Patients with primary headache disorders that are classified as "other primary headache disorders" have presentations with unique diagnostic and management considerations. The disorders are highly recognizable, and an appreciation of the diagnoses will aid clinicians in providing safe and effective care for patients presenting with headache.

Inspiring the future generation in paediatrics during the pandemic – great ormond street hospital summer school 2020

IntroductionGreat Ormond Street Hospital (GOSH) Summer School aims to inspire medical students and junior doctors to follow a career in Paediatrics, especially given the low competition ratio in Paediatrics training applications in the last three years.This year we had to move the conference to a virtual environment due to the outbreak of COVID-19.IssuesWe needed to modify the program to be deliverable as a series of webinars. The Summer School’s capacity was increased to 500 participants (Virtually) from 75 (face to face).We explored ways to maintain interactivity, keep engagement, and fulfill our aim to inspire with a much larger group within the virtual environment. Furthermore, we refined our program to reflect the current pandemic.InterventionsTo reduce digital fatigue, we changed the length of the conference from 2.5 long days to 4 short days. Each day consisted of 3 or 4 webinars and a career panel session. The career panel sessions focus on sharing the individual journey, which was met with great enthusiasm from the participants.We utilized multiple tools to facilitate the interaction with the participants and speakers: Slido (Q and A, poll and quiz), a conference App, social media, and the ‘Raise Hand’ tool within Zoom.MeasurementsThe conference was well attended with zoom data showed 390, 282,305, and 324 along the four days. Slido showed a high level of engagement with a total of 1005 questions posted and 434 active participants. 344 completed the post-conference survey, 80% voted the conference being excellent, and 100% voted for the continuation of delivering the conference online next year.Lessons LearntCOVID-19 compelled us to run our conference digitally, however we have gained a great deal of experience in management, leadership, and education. We learned the necessity of making rapid decisions and flexible leadership to enable ourselves to deliver quality education during the pandemic.

Changes in Students' Achievement Motivation in the Context of the COVID-19 Pandemic: A Function of Extraversion/Introversion?

Students' mental health has been an increased concern since the outbreak of the COVID-19 pandemic. However, academic outcomes have received very little attention. In this study, changes in students' achievement motivation are investigated using an expectancy-value framework. Participants (n = 90) were high school students (grades 9 and 10) who reported on their expectancy and value perceptions in regard to learning before and during the pandemic (i.e., January and November 2020). Changes over time and as a function of extraversion/introversion were analyzed using repeated measures multivariate analyses of variance (MANOVAs). Most perceptions were found to be stable with the exception of interest in learning, which increased as a function of extraversion. Results are discussed in light of relevant pre-pandemic evidence.