A systematic review and meta-analysis of studies exploring prevalence of non-specific anxiety in undergraduate university students.

BACKGROUND: Anxiety is a common mental health problem in the general population, and is associated with functional impairment and negative impacts upon quality of life. There has been increased concern about university students' mental health in recent years, with a wide range of non-specific anxiety rates reported worldwide in undergraduate university students. We aimed to explore prevalence of non-specific anxiety in undergraduate university student populations. METHODS: Four databases were searched to identify studies published between 1980 and 2020 which investigated prevalence of non-specific anxiety in undergraduate university students. Each study's quality was appraised using a checklist. Sub-analyses were undertaken reflecting outcome measure utilized, course of study, location of study, and whether study was before or during the COVID-19 pandemic. RESULTS: A total of 89 studies - representing approx. 130,090 students-met inclusion criteria. Eighty-three were included in meta-analysis, calculating a weighted mean prevalence of 39.65% (95% CI: 35.72%-43.58%) for non-specific anxiety. Prevalence from diagnostic interview studies ranged from 0.3%-20.8% 12-month prevalence. Prevalence varied by outcome measure used to assess non-specific anxiety, the type of course studied by sample, and by study location. In half the studies, being female was associated with being more likely to have higher non-specific anxiety scores and/or screening above thresholds. Few of the included studies met all quality appraisal criteria. CONCLUSION: The results suggest that approximately a third of undergraduate students are experiencing elevated levels of non-specific anxiety. Results from sub-analyses have identified some methodological issues that need consideration in appraising prevalence in this population.

Correcting Disparities in Adolescent Access to Medicines by Promoting Age-Inclusive Research

The average time between regulatory approval and labeling of an innovative medicine for adults and children is nearly a decade.1 Often this is the result of poorly integrated adult and pediatric studies within medicines development programs, which consequently leads to prolonged off-label pediatric use. Furthermore, the conduct of studies in children after adult market approval becomes difficult if not impossible. Experiences during the SARS-CoV-2 pandemic have heightened awareness of this disparity. The fact that most children have been less severely affected by COVID-19 combined with reluctance to include children in early phases of investigational research has contributed to delays in evaluation of potential treatments for those children who present with more severe forms of the disease.2 Our study sought to understand how adolescent inclusion in adult trials is positioned in regulatory guidance since such documents set critical expectations for trial design and regulatory decision-making for innovative medicines. The authors conducted multiple sequential PubMed searches in November 2019 (and repeated in August 2021) utilizing a variety of grouped search terms-including ''pediatric,'' ''paediatric,'' ''adolescent,'' ''adolescence,'' ''regulatory guidance,'' ''guidance,'' ''FDA guidance,'' ''regulatory guideline,'' ''guideline,'' ''EMA guideline,'' and/or ''meta-analysis.'' The searches failed to return any results showing that an analysis of regional regulatory guidance specific to age-inclusive research has been published. It is our understanding that this study represents the first comprehensive analysis of age-inclusive language within regulatory guidance for two globally important health agencies, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The study utilized a qualitative analysis approach to review FDA and EMA regulatory guidance documents assessing their recommendations about adolescent inclusion in clinical trials. The study found that regulatory guidance contained recommendations supporting adolescent inclusion in 32% of FDA and 15% of EMA documents, while 14% and 21%, respectively, were found to be exclusionary. In both regions, more than half of all guidance documents were silent regarding the applicability of adolescentinclusive trial methodologies. Analysis by therapeutic area revealed FDA guidance for infectious diseases and EMA guidance for conditions requiring blood products was the most permissive. A more inclusive approach was identified to disease guidance published by the FDA Oncology Center of Excellence. Our study has identified important opportunities for enhancement of regulatory guidance which, if addressed, can facilitate inclusion of adolescent patients in adult trials to accelerate adolescent access to life-changing medicines. Regulatory guidance plays a critical role in improving the type and the quality of data generated in clinical trials which inform medicines use in diverse patient populations. As pediatric policy reforms have led to significant experience with pediatric medicines development, this should be leveraged to update existing regulatory guidance, fostering scientifically justified inclusion of adolescents in adult clinical trials.

Factors influencing COVID-19 health protective behaviours in Zambian university students with symptoms of low mood.

BACKGROUND: Health protective behaviours are crucial in the prevention of the spread of COVID-19, particularly in university students who typically live and study in large groups. Depression and anxiety are common in students and can impact young people's motivations to follow health advice. The study aims to assess the relationship between mental health and COVID-19 health-protective behaviours in Zambian university students with symptoms of low mood. METHODS: The study was a cross-sectional, online survey of Zambian university students. Participants were also invited to take part in a semi-structured interview to explore views about COVID-19 vaccination. Invitation emails were sent explaining the study aims and directed students who self-identified as having low mood in the past two weeks to an online survey. Measures included COVID-19 preventive behaviours, COVID-19-related self-efficacy, and Hospital and Anxiety Depression scale. RESULTS: A total of 620 students (n=308 female, n=306 male) participated in the study, with a mean participant age of 22.47±3.29 years (range 18-51). Students reported a mean protective behaviour score of 74.09/105 and 74% scored above the threshold for possible anxiety disorder. Three-way ANOVA showed lower COVID-19 protective behaviours in students with possible anxiety disorder (p=.024) and those with low self-efficacy (p<0.001). Only 168 (27%) said they would accept vaccination against COVID-19, with male students being twice as likely to be willing to accept COVID-19 vaccination (p<0.001). Of 50 students interviewed. 30 (60%) expressed fears about the vaccination and 16 (32%) were concerned about a lack of information. Only 8 (16%) participants expressed doubts about effectiveness. CONCLUSION: Students who self-identify as having symptoms of depression have high levels of anxiety. The results suggest that interventions to reduce anxiety and promote self-efficacy might enhance students' COVID-19 protective behaviours. Qualitative data provided insight into the high rates of vaccine hesitancy in this population.

IBRUTINIB AND RITUXIMAB AS FIRST LINE THERAPY FOR MANTLE CELL LYMPHOMA: A MULTICENTRE, REAL-WORLD UK STUDY

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

Self-help Digital Interventions Targeted at Improving Psychological Well-being in Young People With Perceived or Clinically Diagnosed Reduced Well-being: Systematic Review.

BACKGROUND: Levels of well-being are declining, whereas rates of mental health problems remain high in young people. The World Health Organization defines mental health as not merely the absence of mental disorder but also includes social and psychological well-being as integral to positive mental health, highlighting that mental health is applicable to young people with mental health conditions and those without a diagnosis of a mental health condition. Reduced mental well-being have been identified in studies of young people with clinical populations, as well as in populations consisting of nonclinical young people. Self-help digital interventions can be delivered at mass at a low cost and without the need for trained input, thereby facilitating access to support for well-being. Self-help interventions are effective in young people with mental health conditions, but systematic reviews of such studies have been limited to randomized controlled trials, have not included reduced well-being as an inclusion criterion, and do not consider engagement factors such as retention. OBJECTIVE: The objective of this study was to systematically review all controlled studies of digitally delivered, self-administered interventions for young people aged 9 to 25 years, with perceived or clinically diagnosed reduced psychological well-being. Participant retention and effectiveness of the interventions were also explored. METHODS: A systematic search of the PsycInfo, EMBASE, Cochrane, Scopus, and MEDLINE databases from inception to 2021, reference searches of relevant papers, and gray literature was carried out for digitally controlled studies conducted with young people with perceived or clinically diagnosed reduced well-being, aimed at improving psychological well-being. Data were extracted to identify the effectiveness and retention rates of the interventions and the quality of the studies. RESULTS: Overall, 1.04% (12/1153) of studies met the inclusion criteria: 83% (10/12) of studies were randomized controlled trials and 17% (2/12) were controlled pre-post studies. Most (6/12, 50%) studies aimed to improve symptoms of depression; 3 interventions aimed at both anxiety and depressive symptoms and 2 studies aimed at improving social functioning difficulties. Owing to the high risk of bias across interventions and lack of similar outcome measures, a meta-analysis was not conducted. Retention rates across studies were regarded as good, with moderate to high retention. Overall, the findings indicated that predominantly self-administered self-help interventions improved well-being in the areas targeted by the intervention and identified additional areas of well-being that were positively affected by interventions. Few interventions supported psychological well-being that was different from those used by young people with a clinical diagnosis of mental illness or young people from neurodiverse backgrounds. CONCLUSIONS: The findings, along with the advantages of self-help interventions, highlight the need for upscaling self-help interventions to better support vulnerable populations of young people who experience poor psychological well-being. TRIAL REGISTRATION: PROSPERO CRD42019129321; https://tinyurl.com/4fb2t4fz.

OLDER PERSON’S ASSESSMENT SERVICE (OPAS): DELIVERING COMPREHENSIVE GERIATRIC ASSESSMENT (CGA) IN THE EMERGENCY DEPARTMENT (ED)

Introduction Innovative models of service delivery are required to provide Comprehensive Geriatric Assessment for older patients presenting to the Emergency Department with frailty syndromes. Method In 2018, the Older Person’s Assessment Service began a liaison service to the ED, taking referrals from the medical and ED teams for patients who presented with frailty syndromes (falls, cognitive impairment, care dependence, polypharmacy). The service saw 437 patients April–August 2018. 76% of the patients assessed were discharged by utilising available community services, rapid access outpatient follow up and inpatient reablement off the acute site. The service was estimated to avoid 50–80 admissions per month to medicine (saving 17–23 beds a year) and was commissioned as a permanent service. Phase 2 In 2020, a dedicated unit within ED was allocated to OPAS, enabling the acceptance of patients directly from triage and from the Ambulance Service by direct referral. This provided rapid access to specialist assessment, continued access to Elderly Care services, avoided exposure to coronavirus related admissions and the risks of nosocomial infection associated with admission. The service operates from 8 am-4 pm on weekdays. Results Between June 2020 and October 2021, the service saw 1,173 new patients. 988 patients (84.5%) were discharged off the acute site on the day of assessment. 68 (5.79%) patients were admitted to other facilities run by the Health Board (e.g Inpatient Reablement). The average age of an OPAS patient was 83 yrs and had a CFS > 5. Readmission rate at 14 days was 4% (47).Of the 253 patients who were admitted to an inpatient setting, 13.5% (35) contracted nosocomial covid-19. Conclusion The service has been supported and funded to expand into extended weekday hours as a result of this success and there are plans for future 7 day working.

EVALUATION OF FRAILTY DOCUMENTATION PRE AND DURING THE COVID-19 PANDEMIC IN A LARGE REGIONAL CENTRE

Background Identifying frailty can lead to improvements in patient outcomes through interventions such as CGA and prompt discussions around resuscitation and ACP. [Welsh;International Journal of Clinical Practice;2014;290– 293] Frailty is associated with a higher risk of postoperative mortality and morbidity, and mortality due to COVID-19.[Parmar;Annals of Surgery;2021;709–718, Dumitrascu;Journal of the American Geriatrics Society;2021;2, 419– 2, 429] Our audit considers whether the pandemic had any effect on documentation of frailty, and identifies interventions to improve this process. Method We retrospectively reviewed notes to look for elements of social history which identify frailty including mobility, ADLs, and CFS. We conducted a series of spot audits in February 2020 (pre-pandemic), April 2021 (Wave 2), and November 2021 (Wave 3) across surgical and medical wards. Interventions and Results February 2020 This cohort consisted of 62 patients and showed poor documentation across both medicine and surgery with an average of only 21% relevant social history recorded and 0% CFS scoring. Interventions that followed included an educational series by geriatricians and introduction of triaging tools based on CFS in response to the pandemic e.g. Swansea Hip interrogation Fracture Tool (SHiFT). [Cronin;British Orthopaedic Association;2020] April 2021 The relevant documentation improved to an average of 31% in this cohort of 37 patients. Interventions that followed included further educational sessions on frailty, a surgical liaison service, and the appointment of an orthogeriatrician. November 2021 This cohort consisted of 149 patients, average relevant social history continued to improve to 49%. Subgroup analysis showed 76% of orthopaedics patients had a CFS score, including 100% of NOF patients. Conclusion Frailty is important as it is linked to an increased risk of mortality and morbidity. In the pre-pandemic cohort, the results were poor. Improvements were seen after interventions such as educational sessions, pandemic triaging tools, and the surgical liaison service. However, there are still inconsistencies between teams. Future interventions include a CFS app, expansion of the surgical liaison service, and improved proformas.

Impact of the COVID-19 pandemic on the delivery of The European thymus transplantation programme

Background Congenital athymia, due to complete DiGeorge syndrome (cDGS) or rare monogenic disorders affecting thymus development, is associated with profound T-cell lymphopaenia and susceptibility to opportunistic infections. Left untreated, athymia is fatal within 1-2 years. It can be successfully treated by thymus transplantation, using cultured thymic tissue obtained from infant donors when necessarily removed during cardiac surgery. In Europe, thymus transplantation is only offered at our centre. Following increased awareness and progressive international implementation of newborn screening (NBS) for severe combined immunodeficiency (SCID), we received a record number of referrals in 2020. Significant restrictions on worldwide travel and reallocation of healthcare resources during the COVID-19 pandemic resulted in the temporary interruption of international admissions. In order to facilitate the timely admission for this life-saving treatment, we developed a modified care pathway (MCP) to address the challenges identified at local, national and international levels. Objectives Optimisation of resource allocation to prevent negative impacts of delayed treatment in athymic infants during the COVID-19 pandemic. Continued delivery of high quality, complex patient care and positive patient experience through a MCP. Methods We conducted a service evaluation to assess the effectiveness of the MCP and the impact on time-to-admission for transplantation. We completed short interviews with accompanying parents and referring clinicians to survey their experience of the thymus transplantation programme during the pandemic. Results With the support of our Trust and NHS England, a MCP was agreed and implemented to ensure safe transfer, admission and repatriation. We regularly amended our admission protocol to reflect the evolving local and national infection prevention control (IPC) policies. We gained adherence from all referring teams and families, while observing the local requirements of the referring teams in 6 European countries and New Zealand. Due to the limited access to donor tissue, secondary to reduced elective cardiac surgery, admissions required optimised coordination between multidisciplinary teams to allow for thymus transplantation within 20 days of donor tissue collection and culture. From May 2020 to March 2021, 10 patients underwent thymus transplantation, reflecting a 50% increase in activity on previous years. The average time for referral-admission was 5 months. 4 patients were identified by NBS in their respective countries and in line with current SCID management guidelines, 2 of them were transplanted by the age of 4 months. One patient tested positive for SARS-CoV2 on return to their home country and made a full recovery. This prompted further changes in our transfer guidance and local IPC practice. Parental interviews highlighted anxieties around international travel, restricted hospital access for the second parent and non-aligned IPC practices in comparison with referring centres. Equally, they accepted and embraced the additional restrictions in order to access their child's essential and only, treatment option. Conclusions Upon prompt identification of challenges and risks to treatment delay for athymic infants during the COVID-19 pandemic, we overcame them in collaboration with referring centres, multi-disciplinary hospital teams and the patient families, resulting in the successful delivery of a record number of thymus transplant procedures following a MCP, maximising the opportunity for improved long-term outcomes.

Unmasking the impact of COVID-19 on businesses: firm level evidence from across the world

This paper provides a comprehensive assessment of the short-term impact of the COVID-19 pandemic on businesses worldwide with a focus on developing countries. The results are based on a novel data set collected by the World Bank Group and several partner institutions in 51 countries covering more than 100,000 businesses. The paper provides several stylized facts. First, the COVID-19 shock has been severe and widespread across firms, with persistent negative impact on sales. Second, the employment adjustment has operated mostly along the intensive margin (that is leave of absence and reduction in hours), with a small share of firms laying off workers. Third, smaller firms are disproportionately facing greater financial constraints. Fourth, firms are increasingly relying on digital solutions as a response to the shock. Fifth, there is great uncertainty about the future, especially among firms that have experienced a larger drop in sales, which is associated with job losses. These findings provide a better understanding of the magnitude and distribution of the shock, the main channels affecting businesses, and how firms are adjusting. The paper concludes by discussing some avenues for future research.

Consumption of alcohol and other psychoactive drugs during the covid-19 pandemic in the global drug survey: A French perspective

The Global Drug Survey is an online survey that aimed to explore the experience of people who use drugs in general population. This survey is conducted annually between November and December. This special Covid-19 component was conducted over seven weeks, from May to June 2020. The objective of the survey was to retrospectively explore the impact of confinement and the first weeks after lockdown on the consumption of psychoactive products in the general population. The results of the survey show an increase in the number of drinking days, but no increase in binge drinking. For cannabis, use remained relatively stable, although a relative increase compared to other countries was observed. The trends of ecstasy and cocaine uses in particular declined. Finally, benzodiazepines have seen their use increase. The Global Drug Survey notes that the pandemic has changed the patterns of use of psychoactive products, without an increase in deregulated behaviours being observed. People who use drugs have adapted their practices in line with changes in their social environment.

PRO115 A Patient-Centric Approach to Designing a MIXED-Methods Observational Study Involving Adolescents with X-Linked Hypophosphatemia

Objectives: A European, prospective, multi-centre, mixed-methods observational study is in development to investigate treatment transition and disease experience in adolescents with X-Linked Hypophosphatemia (XLH), a rare, genetic life-long phosphate-wasting disorder. To ensure robustness, feasibility and patient-centricity of study design, a UK patient-public involvement (PPI) project was undertaken. Methods: During June 2020, four adolescents (14-18 years), recruited via patient group XLH UK, underwent 1:1 semi-structured 60-minute telephone interviews (following informed consent). Participants described their experience of known symptoms and impacts of XLH identified from the literature and burosumab trials (pain, stiffness, mobility and physical function, tiredness/fatigue, sleep, emotional wellbeing) and then prioritised their importance for measurement. The acceptability of proposed methods for data capture (e.g. use of wearables, smartphone app), recruitment, and retention of participants was also discussed. Responses were summarised narratively in MS Excel to aid future study design. Results: The interference of pain, stiffness and tiredness/fatigue on daily physical activities were identified as key endpoints, alongside modifications to daily activities and socialising for symptom management. Mild symptoms were reported by most participants, either due to effective treatment or reduced activity during COVID-19. One participant was more concerned with emotional wellbeing, relating to self-confidence, and favoured its measurement in studies. No-one reported problematic sleep. All were willing to participate in a 12-month study, answering one daily question using a phone app and wearing a wrist-device daily to capture activity, although night-time use was less acceptable. Recruitment via social media and doctors was perceived as optimal and compensatory monetary vouchers were favoured. Conclusions: This PPI project identified patient-relevant endpoints of pain, stiffness and fatigue/ tiredness to be examined according to their interference of daily physical activities or socialising. Measurement using wearables and smartphones was viewed as acceptable and feasible for adolescents with XLH, which may therefore relieve burden on the healthcare system.

Therapist-Supported Online Interventions for Children and Young People With Tic Disorders: Lessons Learned From a Randomized Controlled Trial and Considerations for Future Practice.

In recent years, research into internet-based cognitive behavioral therapy (iCBT) has suggested that therapist-guided digital interventions have greater engagement, adherence, and effectiveness than self-directed digital therapies. While research has focused on the effectiveness of, and adherence to, these interventions, less attention has been paid to their implementation in practice and what aspects of the therapist role support success. An understanding of the key factors related to the therapist role and intervention delivery is required if these iCBTs are to be applied in routine clinical care and outcomes optimized. In light of the coronavirus disease 2019 (COVID-19) pandemic, there is greater emphasis on allowing patients access to remote therapies. We report the experiences and reflections of 4 therapists and their 2 supervisors in delivering an online, therapist-supported intervention in a randomized controlled trial for children and young people with tic disorders (the Online Remote Behavioural Intervention for Tics [ORBIT] trial). Themes discussed include the importance of training, supervision, creating support documents/manuals, and record keeping. Alongside this are communication strategies used by therapists to encourage patient adherence and treatment effectiveness. These include rapport building, treatment personalization, and suggestions for overcoming non-engagement. These reflections offer important considerations for the delivery of iCBTs as well as implications associated with the implementation of these interventions in existing services and future research studies. We share thoughts on where iCBTs may sit in a stepped care model, how services may deal with comorbid conditions, and the potential role of iCBTs in collecting clinical data.