Challenges and strategies with international recruitment in early phase gene therapy trials

The Children's NIHR Clinical Research Facility at Royal Manchester Children's Hospital has been involved in numerous early phase gene therapy trials for diseases such as GM1 gangliosidosis, Gaucher disease, MPSIIIA and MPSII. These trials have necessitated international recruitment which brings challenges for both site and families. In addition, we also actively recruited participants during the Covid-19 global pandemic, amplifying these challenges. A typical patient journey on one of these trials would involve being approached soon after diagnosis due to the rapid progression of these diseases and the need for early intervention. The family would then relocate to the UK with relatively short notice and commence an intensive period of screening involving a lot of extensive information for them to retain and invasive procedures for the patient. Some of these families will speak no English at all which is an additional barrier to managing the parental anxiety and expectations of the trial and its outcome. Once eligibility is confirmed the families are then faced with an extended stay in the UK without the support of their extended family/community. This impacts parent's employment and other siblings who may or may not be with them and who may also be affected by the same disease. Following administration of the gene therapy, participants then commence intensive follow up often associated with immunosuppressants. Close working with the local clinicians is essential for patient safety and trial integrity. Good engagement with families once they have returned to their home country is vital in obtaining continuing trial data and ensuring retention and compliance with attending future visits. Follow up visits are essential for safety and efficacy data for the progression of gene therapy trials. Travel restrictions brought about by the covid 19 pandemic exacerbated these challenges but with good communication and engagement we have mostly overcome them.

Factors Associated with Food Insecurity Among Health Sciences Students During the COVID-19 Pandemic

This web-based survey explored factors associated with food insecurity (FI) among health sciences students during the COVID-19 pandemic. FI was assessed using the USDA 6-item tool. Multivariable logistic regression was used for data analyses. Of the 816 respondents, 74.7% were female and 22.1% were food insecure. An annual income of <$25,000, housing instability, use of a food pantry over the past 12 months, and receiving financial support from family were independently associated with increased odds of being food insecure even after adjusting for other covariates. Further research exploring FI screening and interventions among health sciences university students is needed.

Emerging and reemerging viral infections in globe with special emphasis in India - A review

It has long been recognized that pathogens, such as viruses, parasites, and other microorganisms, emerge and change over time. Viruses are powerful infectious agents that have co-evolved with humans and are responsible for several serious illnesses in people. There is no herd immunity for most humans, making emerging viruses, particularly the RNA viruses, more dangerous. The high mistake rate of the polymerases that copy the RNA viruses' genomes gives them the ability to adapt to the quickly changing local and global environments. Through mutation (as in the case of Dengue viruses), reassortment (as in the case of influenza viruses), and recombination, they can evolve at a rapid rate (polioviruses). The influenza A viruses (such as H1N1 and H5N1), which have caused numerous outbreaks, epidemics, and pandemics around the world, are the finest example of viruses emerging and reemerging. The complex host-pathogen ecology and the co-evolution of microbes with their hosts are linked to the emergence and reemergence of novel diseases. Human viral illness emergence and reemergence is an ongoing problem that affects a nation's social and economic growth.

Long-COVID and comorbid depression and anxiety two years into the COVID-19 pandemic

Long-COVID, or the persistence of COVID-19 symptoms for months after initial infection, has been shown to impact the lives of those affected. The current study sought to investigate the relationships between long-COVID, COVID-19 related stress, depression, anxiety, and comorbid depression and anxiety outcomes. Data were collected in Winter 2021-2022 from a population of adults enrolled in at least one course across multiple City University of New York (CUNY) campuses. Frequencies and chi-square tests were computed to assess for demographics and relationships to probable diagnoses of depression and anxiety, and binary logistic regressions were computed to assess for the odds of probable comorbid depression and anxiety based on demographics, stressors, and long-COVID. Women participants reported higher odds of probable depression outcomes, and stressor levels were significant correlates of probable anxiety outcomes. Women participants, 3.2 [1.5-6.9], as compared to men, lower-SES participants, 2.16 [1.1-4.2], as compared to higher-SES participants, participants with higher COVID-19 related stress levels, 4.8 [2.0-12.0], as compared to those with low levels, and participants with long-COVID, 3.7 [1.9-7.0], as compared to those without, all had higher odds of probable comorbid depression and anxiety. Findings highlight the importance of social location, stress, and long-COVID, in tandem, as correlates of psychological health during the shifting pandemic.

Digital mental health and employment - Lessons from the Australian experience

Background and objectives: This paper reviews Australia's take-up of digital mental health interventions, including some specific reference to their application in relation to employment. Use of these interventions in Australia was already significant. Under COVID-19 they have exploded. The Australian experience offers useful lessons for European and other countries, and these are summarised. Methods: This paper presents a narrative review of key texts, resources, policies and reports, from government and other sources. It also presents data reflecting the take-up of digital mental health services and the employment of people with a mental illness in Australia. Results: We present data showing the explosion in uptake of digital mental health services. There is very limited evidence about the impact of these services in improving employment outcomes for people with a mental illness in Australia. The Government has moved to make them a permanent feature of mental health care, in addition to traditional face-to-face care. Conclusion: Key lessons emerge from the Australian experience, including the need for target clarity;the importance of blending digital services into broader frameworks of mental health care;the need for quality and safety standards to be developed and applied to digital services;and the need for better evaluation of the outcomes of digital interventions in the workplace. The digital mental health genie is out of the bottle. New capacity for evaluation of the outcomes of digital mental health services is vital to ensure value and quality of such investments. © 2022 Asociación Universitaria de Zaragoza para el Progreso de la Psiquiatría y la Salud Mental

Pituitary apoplexy following adenoviral vector-based COVID-19 vaccination

Pituitary apoplexy (PA) may complicate the course of coronavirus disease 2019 (COVID-19), posing a potential threat to life. Among vaccines designed to prevent COVID-19, there are those adenoviral vector-based, such as Vaxzevria® (formerly COVID-19 Vaccine AstraZeneca). The product insert states that it can cause very rare coagulation disorders, in particular thrombosis with thrombocytopenia syndrome in some cases accompanied by bleeding, cerebrovascular venous or sinus thrombosis, and thrombocytopenia, including immune thrombocytopenia, also associated with bleeding. Here, we report the onset of PA after Vaxzevria® in a 28-year-old healthy Caucasian female, who experienced long-lasting tension-type headache, hyperprolactinemia and menstrual changes, without thrombocytopenia or thrombosis.

Safety of COVID-19 Vaccines

By June 1, 2022, there were 38 prophylactic COVID-19 vaccines approved in 197 countries around the world. The ongoing approval of new vaccines and the accumulation of more than a year's worth of data on their use give particular importance to the consolidation and analysis of information on the safety of such vaccines. The aim of study was to analyse the information on adverse events after immunisation (AEFIs) with coronavirus vaccines in the individual case safety reports entered into the VigiBase database by June 1, 2022. Materials and methods: the author analysed safety reports retrieved from VigiBase through the VigiLyze interface in the expert access mode. The search was carried out using the generic keyword "Covid-19 vaccine” in combination with the trade names of all 38 coronavirus vaccines. Results: the article presents consolidated information on the number and content of the safety reports on COVID-19 vaccines. The author noted that the reports were characterised by a high level of information completeness and quality, which could be due to the fact that the main reporters were the countries with developed pharmacovigilance systems. The analysis of patient complaints showed that the reported symptoms of AEFIs coincided with the manifestations of side effects of the vaccines included in the package leaflets. The author carried out a review of the cases of serious AEFIs and the cases of adverse events of special interest requiring additional monitoring after immunisation. It revealed a positive correlation of individual vaccines with the cases of somnolence in post-COVID-19 patients. Conclusions: the data obtained on the global safety of coronavirus vaccines may be of practical interest to doctors, researchers, developers, and healthcare regulators.

Psychological analysis of injuries in a first category softball national championship in Cuba

Introduction: the systematic analysis of the relationships between relevant psychological variables for sports performance and injuries is essential to contribute to their prevention in specific sports. Material and methods: a descriptive-correlational and cross-sectional study was carried out in the first category women's national softball championship in Cuba. 88 athletes participated with an average chronological age of 22.91 (SD=6.13) and a sports experience of 10.83 years (SD=4.92). A specific questionnaire, the Competitive Sport Anxiety Inventory and the Psychological Inventory of Sport Execution was applied. Descriptive statistics and Kendall's Tau_b nonparametric correlation coefficient was used for data analysis. Results: A high injury load was verified with a low perception of the role of psychological factors in its etiology, as well as a notable occurrence of new injuries with negative emotional repercussions. Negative correlations of self-confidence, negative coping control, visual-imaginative control, positive coping control, and attitude control with history of injuries were obtained. The high anxiety showed significant relationships with previous injuries and new injuries during the analyzed competition. Conclusions: the findings are especially congruent with previous results in elite softball players, although new and greater relationships between variables were determined. All this means that stimulating psychological skills to control anxiety in competition could contribute to the prevention of injuries. However, longitudinal analyzes are required to confirm the predictive role of these variables before proposing psychological interventions in this regard.

ENDOTHELIAL INFLAMMATION AND DYSFUNCTION INDUCED BY SARS-COV-2 SPIKE PROTEIN 1 INVOLVE ADAM17 AND INTERFERON ACTIVATION PATHWAYS

Objective: COVID19 is associated with vascular inflammation. IFN-alpha (IFNa) and IFN-lambda3 (IFNl3) are potent cytokines produced in viral infections. Their effects involve interferon-stimulated genes (ISGs) and may influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFN-activated pathways Design and methods: Human ECs were stimulated with S1P (1 mg/mL), IFNa (100ng/mL) or IFNl3 (100IU/mL). Because ACE2, ADAM17 and TMPRSS2 are important for SARS-CoV-2 infection, we used inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 mM). Gene and protein expression was investigated by real-time PCR and immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive (LinA3) mice and in ISG15-deficient (ISG15KO) mice. Results: S1P increased expression of IFNa (3-fold), IFNl3 (4-fold) and ISGs (2-fold) in EC (p < 0.05). EC responses to IFNa (ISG15: 16-fold) were greater than to IFNl3 (ISG15: 1.7-fold) (p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFa (6.2-fold) and IL-1b (3.3-fold), effects that were amplified by IFNs. Only the ADAM17 inhibitor marimastat inhibited S1P effects. IFNa and IFNl3 increase protein expression of ADAM17 (27%) and TMPRSS2 (38%). No changes were observed on ACE2 expression. This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). EC production of IL-6 was increased by IFNa (1,230pg/mL) and IFNl3 (1,124pg/mL) vs control (591pg/mL). Nitric oxide generation and eNOS phosphorylation (Ser1177) were reduced by IFNa (40%) and IFNl3 (40%). Vascular functional responses demonstrated that endothelium-dependent vasorelaxation (% Emax) in vessels from WT-mice stimulated with IFNa (67%) and IFNl3 (71%) were reduced vs control (82%) (p < 0.05). Responses were not altered in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNa (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN) (p < 0.05). Conclusions: In ECs, S1P, IFNa and IFNl3 increased ISG15 and IL-6 by mechanisms dependent on ADAM17. IFNs amplifies endothelial cell inflammatory responses and induced vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This may be especially important in the presence of cardiovascular risk factors, including hypertension.

Pandemic modelling: The impact of social distancing in Nordic countries

Background: Without pharmacologic interventions, the preferred strategy to combat COVID-19 is to slow the virus' spread via social distancing measures. The components of social distancing include: school closure, restrictions on gatherings, non-essential business closure, stay at home orders and limitations on travel. Most countries have implemented many of these restrictions. Conversely, Sweden has not initiated these restrictions and instead has recommended that citizens avoid mass gatherings, which presents an opportunity to examine the effects of the components of social distancing on mortality in Nordic countries. Purpose: Investigate the impact of social distancing measures on fatalities associated with COVID-19. Method: COVID-19 fatalities, as reported by the World Health Organisation, were recorded for each of the Nordic countries from 6th February 2020 to 30th April 2020. The fatalities were compared using a Cox proportional hazard regression analysis. Results: The normalised fatalities ranged significantly (1.87 to 129 deaths/population/km2) in the Nordic countries. Sweden was found to have a significantly higher risk of COVID-19 related mortality at the α=0.05 level as compared to Finland (HR=0.15;p<0.001) and Norway and Denmark (HR=0.23;p=0.002). Conclusion: The population-density normalised mortality in Sweden was significantly greater than other Nordic countries, possibly due to differences in the implementation of social distancing policies.

Mass testing for asymptomatic COVID-19 infection among healthcare workers at a large Canadian hospital

Background: The perceived risk of coronavirus disease 2019 (COVID-19) infection for healthcare workers (HCWs) is high. Although testing has focused on symptomatic HCWs, asymptomatic testing is considered by some to be an important strategy to limit occupational spread. Evidence on the results of large asymptomatic testing strategies in healthcare is, however, limited. This study examines the uptake and positivity of COVID-19 testing in a voluntary asymptomatic testing campaign at a large Canadian hospital. Method: In addition to testing HCWs with symptoms, all asymptomatic staff were offered a COVID-19 test at Trillium Health Partners, a large Ontario hospital, from May 27 to June 15, 2020. Testing was offered in four waves, corresponding to the likelihood of exposure to COVID-19-positive patients. The mass asymptomatic testing campaign was offered when the hospital's community test positivity rate had declined to 5%. Results: Since March 16, the hospital has tested 51.3% of its 10,143-person workforce at least once. In the asymptomatic testing campaign for HCWs between May 27 and June 15, 27% of clinical and non-clinical staff received testing. No large differences were found in the proportions of clinical HCWs tested by their exposure to COVID-19-positive patients. In this campaign, 0.2% of asymptomatic HCWs tested positive. However, these individuals either had mild symptoms at testing and did not self-identify or became symptomatic after testing. Conclusions: At this large hospital with declining community prevalence, a mass asymptomatic testing campaign of HCWs found they had a very low likelihood of testing positive for COVID-19.

Application of machine learning approaches to predict the impact of ambient air pollution on outpatient visits for acute respiratory infections

With a remarkable increase in industrialization among fast-developing countries, air pollution is rising at an alarming rate and has become a public health concern. The study aims to examine the effect of air pollution on patient's hospital visits for respiratory diseases, particularly Acute Respiratory Infections (ARI). Outpatient hospital visits, air pollution and meteorological parameters were collected from March 2018 to October 2021. Eight machine learning algorithms (Random Forest model, K-Nearest Neighbors regression model, Linear regression model, LASSO regression model, Decision Tree Regressor, Support Vector Regression, X.G. Boost and Deep Neural Network with 5-layers) were applied for the analysis of daily air pollutants and outpatient visits for ARI. The evaluation was done by using 5-cross-fold confirmations. The data was randomly divided into test and training data sets at a scale of 1:2, respectively. Results show that among the studied eight machine learning models, the Random Forest model has given the best performance with R2 = 0.606, 0.608 without lag and 1-day lag respectively on ARI patients and R2 = 0.872, 0.871 without lag and 1-day lag respectively on total patients. All eight models did not perform well with the lag effect on the ARI patient dataset but performed better on the total patient dataset. Thus, the study did not find any significant association between ARI patients and ambient air pollution due to the intermittent availability of data during the COVID-19 period. This study gives insight into developing machine learning programs for risk prediction that can be used to predict analytics for several other diseases apart from ARI, such as heart disease and other respiratory diseases. © 2022 Elsevier B.V.

106. Adolescent Social Networks and School Engagement Across the High School Transition

Purpose: Attending and meaningfully engaging in school is a critical component of adolescence with broad implications for future health and well-being. Social network analysis offers powerful techniques to examine how the quality and structure of social relationships affect adolescent health and education. Peer and adult relationships impact adolescent health-affecting behaviors such as substance use and violence involvement, with potential for beneficial or deleterious effects. Social networks may similarly confer risk or protection for school engagement, an urgent issue of adolescent health considering COVID-19-related school disruptions. We describe adolescent social network quality and structure and examine associations between social network characteristics and school engagement during the transition from middle to high school. Methods: We analyzed data from an ongoing randomized trial of the Advancement via Individual Determination (AVID) college readiness program across 5 public high schools in Southern California. Participants completed baseline surveys at the end of 8th/beginning of 9th grade and follow-up surveys at the end of 9th grade. The Student Engagement Instrument assessed school engagement and egocentric social network surveys assessed adolescent social network quality (e.g., network composition, peer behavior) and structure (e.g., centrality, density). Multilevel mixed-effects models examined associations between baseline social network characteristics and concurrent and future school engagement. Models were adjusted for gender, ethnicity, prior AVID participation, study arm, and baseline school engagement as appropriate. Results: Baseline participants (n=431) were 60.6% female and 82.8% identified as Latinx. 418 participants completed follow-up surveys;retention rate=97.0%. Mean school engagement was 3.26 at baseline (SD=0.53;range 1-4) and 3.14 at follow-up (SD=0.52). Across all individuals in participants' social networks, 68.7% were peers, 24.5% were adults, and 55.4% were identified as sources of support. Across all peers in participants' social networks, 9.1% engaged in substance use and 82.6% were highly engaged in school. Overall social network characteristics associated with concurrent school engagement included a greater proportion of coaches (β=3.01;95%CI 0.01-6.02) and sources of support (β=0.20;95%CI 0.03-0.37). Peer social network characteristics associated with concurrent school engagement included a greater proportion of peers highly engaged in school (β=0.40;95%CI 0.20-060), a lower proportion of peers who use substances (β=-0.25;95%CI -0.50-0.00), and lower peer network density (β=-0.40;95%CI -0.72–0.08). Overall social network characteristics associated with future school engagement included a greater proportion of teachers (β=0.94;95%CI 0.05-1.82) and sources of support (β=0.28;95%CI 0.11-0.44). Peer social network characteristics associated with future school engagement included a greater proportion of peer sources of support (β=0.17;95%CI 0.03-0.32) and a lower proportion of peers who disrupt class (β=-0.29;95%CI -0.56–0.03). Conclusions: Building or bolstering connections to supportive peers and adults may serve to enhance adolescents' school engagement. Similar to other adolescent health-affecting behaviors, school engagement may be positively or negative influenced by the behaviors of peers in adolescents' social circles. Network-based interventions that target multiple associated social network-mediated behaviors, such as school engagement and substance use, may be particularly beneficial to adolescent health. Sources of Support: NIH/NICHD (T32HD071834), UPMC Children's Hospital of Pittsburgh Scholar Award, NIH/NIDA (1K23DA040733-01A1), Robert Wood Johnson Foundation (E4A 74086).

Outcomes of elective cancer surgery in COVID-19 survivors: An observational study

Background and Objectives: Guidelines recommend deferral of elective surgery after COVID-19. Delays in cancer surgeries may affect outcomes. We examined perioperative outcomes of elective cancer surgery in COVID-19 survivors. The primary objective was 30-day all-cause postoperative mortality. The secondary objectives were 30-day morbidity, and its association with COVID-19 severity, and duration between COVID-19 and surgery. Methods: We collected data on age, gender, comorbidities, COVID-19 severity, preoperative investigations, surgery performed, and intra and postoperative outcomes in COVID-19 survivors who underwent elective cancer surgery at a tertiary-referral cancer center. Results: Three hundred and forty-eight COVID-19 survivors presented for elective cancer surgery. Of these, 332/348 (95%) patients had mild COVID-19 and 311 (89%) patients underwent surgery. Among patients with repeat investigations, computerized tomography scan of the thorax showed the maximum new abnormalities (30/157, 19%). The 30-day all-cause mortality was 0.03% (1/311) and 30-day morbidity was 17% (54/311). On multivariable analysis, moderate versus mild COVID-19 (odds ratio [OR]: 1.95;95% confidence interval [CI]: 0.52–7.30;p = 0.32) and surgery within 7 weeks of COVID-19 (OR: 0.61;95% CI: 0.33–1.11;p = 0.10) were not associated with postoperative morbidity. Conclusions: In patients who recover from mild to moderate COVID-19, elective cancer surgery can proceed safely even within 7 weeks. Additional preoperative tests may not be indicated in these patients. © 2022 Wiley Periodicals LLC.

Controlled release nanomedicine (CRNM) of aspirin using "biomimetic niosomal nanoparticles (BNNs)”for Covid-19 and cardiovascular treatment: DOE based optimization

Biomimetic strategies can be adopted to improve biopharmaceutical aspects. Subsequently, Biomimetic reconstitutable pegylated amphiphilic lipid nanocarriers have high translational potential for systemic controlled drug delivery;however, such an improvised system for systemic aspirin delivery exploring nanotechnology is not available. Systemic administration of aspirin and its controlled delivery can significantly control blood clotting events, leading to stroke, which has immediate applications in cardiovascular diseases and Covid-19. In this work, we are developing aspirin sustained release pegylated amphiphilic self-assembling nanoparticles to develop reconstitutable aspirin injections by solvent-based co-precipitation method with phase inversion technique that leads to novel "biomimetic niosomal nanoparticles (BNNs).” DOE led optimization is done to develop Design of space for optimized particles. Upon reconstitution of solid powder, the particle size was 144.8 ± 12.90 nm with a surface charge of -29.2 ± 2.24 mV. The entrapment efficiency was found to be 49 ± 0.15%, wherein 96.99 ± 1.57% of the drug was released in 24hr showing super case II transport-based drug release mechanism. The formulation has the least hemolysis while showing significant suppression of platelet aggregation. MTT assay does not show any significant cytotoxicity. This is a potential nanoparticle that can be explored for developing aspirin injection, which is not available.