Veklury® (remdesivir) formulations inhibit initial membrane-coupled events of SARS-CoV-2 infection due to their sulfobutylether-ß-cyclodextrin content.

BACKGROUND AND PURPOSE: Despite its contradictory clinical performance, remdesivir (Veklury®) has a pivotal role in COVID-19 therapy. Possible contributions of the vehicle, sulfobutylether-ß-cyclodextrin (SBECD) to Veklury® effects have been overlooked. The powder and solution formulations of Veklury® are treated equivalently despite their different vehicle content. Our objective was to study Veklury® effects on initial membrane-coupled events of SARS-CoV-2 infection focusing on the cholesterol depletion-mediated role of SBECD. EXPERIMENTAL APPROACH: Using time-correlated flow cytometry and quantitative three-dimensional confocal microscopy, we studied early molecular events of SARS-CoV-2-host cell membrane interactions. KEY RESULTS: Veklury® and different cholesterol-depleting cyclodextrins (CDs) reduced binding of the spike receptor-binding domain (RBD) to ACE2 and spike trimer internalization for Wuhan-Hu-1, Delta and Omicron variants. Correlations of these effects with cholesterol-dependent changes in membrane structure and decreased lipid raft-dependent ACE2-TMPRSS2 interaction establish that SBECD is not simply a vehicle but also an effector along with remdesivir due to its cholesterol-depleting potential. Veklury® solution inhibited RBD binding more efficiently due to its twice higher SBECD content. The CD-induced inhibitory effects were more prominent at lower RBD concentrations and in cells with lower endogenous ACE2 expression, indicating that the supportive CD actions can be even more pronounced during in vivo infection when viral load and ACE expression are typically low. CONCLUSION AND IMPLICATIONS: Our findings call for the differentiation of Veklury® formulations in meta-analyses of clinical trials, potentially revealing neglected benefits of the solution formulation, and also raise the possibility of adjuvant cyclodextrin (CD) therapy, even at higher doses, in COVID-19.

Self-Harm in Children and Adolescents Who Presented at Emergency Units During the COVID-19 Pandemic: An International Retrospective Cohort Study.

OBJECTIVE: To compare psychiatric emergencies and self-harm at emergency departments (EDs) 1 year into the pandemic, to early pandemic and pre-pandemic, and to examine the changes in the characteristics of self-harm presentations. METHOD: This retrospective cohort study expanded on the Pandemic-Related Emergency Psychiatric Presentations (PREP-kids) study. Routine record data in March to April of 2019, 2020, and 2021 from 62 EDs in 25 countries were included. ED presentations made by children and adolescents for any mental health reasons were analyzed. RESULTS: Altogether, 8,174 psychiatric presentations were recorded (63.5% female; mean [SD] age, 14.3 [2.6] years), 3,742 of which were self-harm presentations. Rate of psychiatric ED presentations in March to April 2021 was twice as high as in March to April 2020 (incidence rate ratio [IRR], 1.93; 95% CI, 1.60-2.33), and 50% higher than in March to April 2019 (IRR, 1.51; 95% CI, 1.25-1.81). Rate of self-harm presentations doubled between March to April 2020 and March to April 2021 (IRR, 1.98; 95% CI, 1.68-2.34), and was overall 1.7 times higher than in March to April 2019 (IRR, 1.70; 95% CI, 1.44-2.00). Comparing self-harm characteristics in March to April 2021 with March to April 2019, self-harm contributed to a higher proportion of all psychiatric presentations (odds ratio [OR], 1.30; 95% CI, 1.05-1.62), whereas female representation in self-harm presentations doubled (OR, 1.98; 95% CI, 1.45-2.72) and follow-up appointments were offered 4 times as often (OR, 4.46; 95% CI, 2.32-8.58). CONCLUSION: Increased pediatric ED visits for both self-harm and psychiatric reasons were observed, suggesting potential deterioration in child mental health. Self-harm in girls possibly increased and needs to be prioritized. Clinical services should continue using follow-up appointments to support discharge from EDs. DIVERSITY & INCLUSION STATEMENT: One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Effectiveness and Waning of Protection With Different SARS-CoV-2 Primary and Booster Vaccines During the Delta Pandemic Wave in 2021 in Hungary (HUN-VE 3 Study).

Background: In late 2021, the pandemic wave was dominated by the Delta SARS-CoV-2 variant in Hungary. Booster vaccines were offered for the vulnerable population starting from August 2021. Methods: The nationwide HUN-VE 3 study examined the effectiveness and durability of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection, Covid-19 related hospitalization and mortality during the Delta wave, compared to an unvaccinated control population without prior SARS-CoV-2 infection. Results: The study population included 8,087,988 individuals who were 18-100 years old at the beginning of the pandemic. During the Delta wave, after adjusting for age, sex, calendar day, and chronic diseases, vaccine effectiveness (VE) of primary vaccination against registered SARS-CoV-2 infection was between 11% to 77% and 18% to 79% 14-120 days after primary immunization in the 16-64 and 65-100 years age cohort respectively, while it decreased to close to zero in the younger age group and around 40% or somewhat less in the elderly after 6 months for almost all vaccine types. In the population aged 65-100 years, we found high, 88.1%-92.5% adjusted effectiveness against Covid-19 infection after the Pfizer-BioNTech, and 92.2%-95.6% after the Moderna booster dose, while Sinopharm and Janssen booster doses provided 26.5%-75.3% and 72.9%-100.0% adjusted VE, respectively. Adjusted VE against Covid-19 related hospitalization was high within 14-120 days for Pfizer-BioNTech: 76.6%, Moderna: 83.8%, Sputnik-V: 78.3%, AstraZeneca: 73.8%, while modest for Sinopharm: 45.7% and Janssen: 26.4%. The waning of protection against Covid-19 related hospitalization was modest and booster vaccination with mRNA vaccines or the Janssen vaccine increased adjusted VE up to almost 100%, while the Sinopharm booster dose proved to be less effective. VE against Covid-19 related death after primary immunization was high or moderate: for Pfizer-BioNTech: 81.5%, Moderna: 93.2%, Sputnik-V: 100.0%, AstraZeneca: 84.8%, Sinopharm: 58.6%, Janssen: 53.3%). VE against this outcome also showed a moderate decline over time, while booster vaccine types restored effectiveness up to almost 100%, except for the Sinopharm booster. Conclusions: The HUN-VE 3 study demonstrated waning VE with all vaccine types for all examined outcomes during the Delta wave and confirmed the outstanding benefit of booster vaccination with the mRNA or Janssen vaccines, and this is the first study to provide clear and comparable effectiveness results for six different vaccine types after primary immunization against severe during the Delta pandemic wave.

Effectiveness and Waning of Protection With Different SARS-CoV-2 Primary and Booster Vaccines During the Delta Pandemic Wave in 2021 in Hungary (HUN-VE 3 Study)

Background In late 2021, the pandemic wave was dominated by the Delta SARS-CoV-2 variant in Hungary. Booster vaccines were offered for the vulnerable population starting from August 2021. Methods The nationwide HUN-VE 3 study examined the effectiveness and durability of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection, Covid-19 related hospitalization and mortality during the Delta wave, compared to an unvaccinated control population without prior SARS-CoV-2 infection. Results The study population included 8,087,988 individuals who were 18–100 years old at the beginning of the pandemic. During the Delta wave, after adjusting for age, sex, calendar day, and chronic diseases, vaccine effectiveness (VE) of primary vaccination against registered SARS-CoV-2 infection was between 11% to 77% and 18% to 79% 14–120 days after primary immunization in the 16–64 and 65–100 years age cohort respectively, while it decreased to close to zero in the younger age group and around 40% or somewhat less in the elderly after 6 months for almost all vaccine types. In the population aged 65–100 years, we found high, 88.1%–92.5% adjusted effectiveness against Covid-19 infection after the Pfizer-BioNTech, and 92.2%–95.6% after the Moderna booster dose, while Sinopharm and Janssen booster doses provided 26.5%–75.3% and 72.9%–100.0% adjusted VE, respectively. Adjusted VE against Covid-19 related hospitalization was high within 14–120 days for Pfizer-BioNTech: 76.6%, Moderna: 83.8%, Sputnik-V: 78.3%, AstraZeneca: 73.8%, while modest for Sinopharm: 45.7% and Janssen: 26.4%. The waning of protection against Covid-19 related hospitalization was modest and booster vaccination with mRNA vaccines or the Janssen vaccine increased adjusted VE up to almost 100%, while the Sinopharm booster dose proved to be less effective. VE against Covid-19 related death after primary immunization was high or moderate: for Pfizer-BioNTech: 81.5%, Moderna: 93.2%, Sputnik-V: 100.0%, AstraZeneca: 84.8%, Sinopharm: 58.6%, Janssen: 53.3%). VE against this outcome also showed a moderate decline over time, while booster vaccine types restored effectiveness up to almost 100%, except for the Sinopharm booster. Conclusions The HUN-VE 3 study demonstrated waning VE with all vaccine types for all examined outcomes during the Delta wave and confirmed the outstanding benefit of booster vaccination with the mRNA or Janssen vaccines, and this is the first study to provide clear and comparable effectiveness results for six different vaccine types after primary immunization against severe during the Delta pandemic wave.

Booster Vaccination Decreases 28-Day All-Cause Mortality of the Elderly Hospitalized Due to SARS-CoV-2 Delta Variant.

(1) Background: SARS-CoV-2 infections are associated with an increased risk of hospital admissions especially in the elderly (age ≥ 65 years) and people with multiple comorbid conditions. (2) Methods: We investigated the effect of additional booster vaccinations following the primary vaccination series of mRNA, inactivated whole virus, or vector vaccines on infections with the SARS-CoV-2 delta variant in the total Hungarian elderly population. The infection, hospital admission, and 28-day all-cause mortality of elderly population was assessed. (3) Results: A total of 1,984,176 people fulfilled the criteria of elderly including 299,216 unvaccinated individuals, while 1,037,069 had completed primary vaccination and 587,150 had obtained an additional booster. The primary vaccination series reduced the risk of infection by 48.88%, the risk of hospital admission by 71.55%, and mortality by 79.87%. The booster vaccination had an additional benefit, as the risk of infection, hospital admission, and all-cause mortality were even lower (82.95%; 92.71%; and 94.24%, respectively). Vaccinated patients needing hospitalization suffered significantly more comorbid conditions, indicating a more vulnerable population. (4) Conclusions: Our data confirmed that the primary vaccination series and especially the booster vaccination significantly reduced the risk of the SARS-CoV-2 delta-variant-associated hospital admission and 28-day all-cause mortality in the elderly despite significantly more severe comorbid conditions.

Nationwide Effectiveness of First and Second SARS-CoV2 Booster Vaccines During the Delta and Omicron Pandemic Waves in Hungary (HUN-VE 2 Study).

Background: In Hungary, the pandemic waves in late 2021 and early 2022 were dominated by the Delta and Omicron SARS-CoV-2 variants, respectively. Booster vaccines were offered with one or two doses for the vulnerable population during these periods. Methods and Findings: The nationwide HUN-VE 2 study examined the effectiveness of primary immunization, single booster, and double booster vaccination in the prevention of Covid-19 related mortality during the Delta and Omicron waves, compared to an unvaccinated control population without prior SARS-CoV-2 infection during the same study periods. The risk of Covid-19 related death was 55% lower during the Omicron vs. Delta wave in the whole study population (n=9,569,648 and n=9,581,927, respectively; rate ratio [RR]: 0.45, 95% confidence interval [CI]: 0.44-0.48). During the Delta wave, the risk of Covid-19 related death was 74% lower in the primary immunized population (RR: 0.26; 95% CI: 0.25-0.28) and 96% lower in the booster immunized population (RR: 0.04; 95% CI: 0.04-0.05), vs. the unvaccinated control group. During the Omicron wave, the risk of Covid-19 related death was 40% lower in the primary immunized population (RR: 0.60; 95% CI: 0.55-0.65) and 82% lower in the booster immunized population (RR: 0.18; 95% CI: 0.16-0.2) vs. the unvaccinated control group. The double booster immunized population had a 93% lower risk of Covid-19 related death compared to those with only one booster dose (RR: 0.07; 95% CI. 0.01-0.46). The benefit of the second booster was slightly more pronounced in older age groups. Conclusions: The HUN-VE 2 study demonstrated the significantly lower risk of Covid-19 related mortality associated with the Omicron vs. Delta variant and confirmed the benefit of single and double booster vaccination against Covid-19 related death. Furthermore, the results showed the additional benefit of a second booster dose in terms of SARS-CoV-2 infection and Covid-19 related mortality.

TikTok and tics: the possible role of social media in the exacerbation of tics during the COVID lockdown.

Background and purpose: Over the past year, many cases with newly onset or significantly exacerbated tic disorders were observed worldwide, where some aspects of the clinical presentation or the symptomatology were atypical for established tic diagnoses. Our purpose was to describe the atypical cases and raise relevant diagnostic issues. Methods: Consecutive cases with atypical tic presentations were documented. Results: Five atypical tic cases are described. These cases shared some common characteristics, most notably the fact that all of them had been exposed to online presentation of ticking behaviour on social media platforms prior to the de novo development or exacerbation of their tics. Even though the order of events suggests causality and therefore the diagnosis of a functional tic disorder, unambiguous criteria for classifying atypical tics as functional symptoms are lacking. Differentiating neurodevelopmental and functional tics in childhood is currently problematic. Conclusion: Based on the currently unresolved issues in differential diagnosis, the importance of watchful waiting and behavioural interventions is highlighted to avoid unwarranted pharmacotherapy.

Booster Vaccination Decreases 28-Day All-Cause Mortality of the Elderly Hospitalized Due to SARS-CoV-2 Delta Variant

(1) Background: SARS-CoV-2 infections are associated with an increased risk of hospital admissions especially in the elderly (age ≥65 years) and people with multiple comorbid conditions. (2) Methods: We investigated the effect of additional booster vaccinations following the primary vaccination series of mRNA, inactivated whole virus, or vector vaccines on infections with the SARS-CoV-2 delta variant in the total Hungarian elderly population. The infection, hospital admission, and 28-day all-cause mortality of elderly population was assessed. (3) Results: A total of 1,984,176 people fulfilled the criteria of elderly including 299,216 unvaccinated individuals, while 1,037,069 had completed primary vaccination and 587,150 had obtained an additional booster. The primary vaccination series reduced the risk of infection by 48.88%, the risk of hospital admission by 71.55%, and mortality by 79.87%. The booster vaccination had an additional benefit, as the risk of infection, hospital admission, and all-cause mortality were even lower (82.95%;92.71%;and 94.24%, respectively). Vaccinated patients needing hospitalization suffered significantly more comorbid conditions, indicating a more vulnerable population. (4) Conclusions: Our data confirmed that the primary vaccination series and especially the booster vaccination significantly reduced the risk of the SARS-CoV-2 delta-variant-associated hospital admission and 28-day all-cause mortality in the elderly despite significantly more severe comorbid conditions.

Lockdown stringency and paediatric self-harm presentations during COVID-19 pandemic: retrospective cohort study.

BACKGROUND: Lockdown during the pandemic has had significant impacts on public mental health. Previous studies suggest an increase in self-harm and suicide in children and adolescents. There has been little research on the roles of stringent lockdown. AIMS: To investigate the mediating and predictive roles of lockdown policy stringency measures in self-harm and emergency psychiatric presentations. METHOD: This was a retrospective cohort study. We analysed data of 2073 psychiatric emergency presentations of children and adolescents from 23 hospital catchment areas in ten countries, in March to April 2019 and 2020. RESULTS: Lockdown measure stringency mediated the reduction in psychiatric emergency presentations (incidence rate ratio of the natural indirect effect [IRRNIE] = 0.41, 95% CI [0.35, 0.48]) and self-harm presentations (IRRNIE = 0.49, 95% CI [0.39, 0.60]) in 2020 compared with 2019. Self-harm presentations among male and looked after children were likely to increase in parallel with lockdown stringency. Self-harm presentations precipitated by social isolation increased with stringency, whereas school pressure and rows with a friend became less likely precipitants. Children from more deprived neighbourhoods were less likely to present to emergency departments when lockdown became more stringent. CONCLUSIONS: Lockdown may produce differential effects among children and adolescents who self-harm. Development in community or remote mental health services is crucial to offset potential barriers to access to emergency psychiatric care, especially for the most deprived youths. Governments should aim to reduce unnecessary fear of help-seeking and keep lockdown as short as possible. Underlying mediation mechanisms of stringent measures and potential psychosocial inequalities warrant further research.

The Porto European Cancer Research Summit 2021.

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures - namely translational research, clinical/prevention trials and outcomes research - were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.

Pandemic-related emergency psychiatric presentations for self-harm of children and adolescents in 10 countries (PREP-kids): a retrospective international cohort study.

To examine the differences in hospital emergency psychiatric presentations for self-harm of children and adolescents during the covid-19 lockdown in March and April 2020 compared with the same period in 2019. Retrospective cohort study. We used electronic patient records from 23 hospital emergency departments in ten countries grouped into 14 areas. We examined data on 2073 acute hospital presentations by 1795 unique children and adolescents through age 18. We examined the total number of emergency psychiatric hospital presentations and the proportion of children and adolescents presenting with severe self-harm as our two main outcome measures. In addition, we examined sociodemographic and clinical characteristics and clinical management variables for those presenting with self-harm. To compare the number of hospital presentations between 2020 and 2019 a negative binomial model was used. For other variables, individual participant data (IPD) meta-analyses were carried out. Emergency psychiatric hospital presentations decreased from 1239 in 2019 to 834 in 2020, incident rate ratio 0.67, 95% CI 0.62-0.73; p < 0.001. The proportion of children and adolescents presenting with self-harm increased from 50% in 2019 to 57% in 2020, odds ratio 1.33, 1.07-1.64; p = 0.009 but there was no difference in the proportion presenting with severe self-harm. Within the subpopulation presenting with self-harm the proportion of children and adolescents presenting with emotional disorders increased from 58 to 66%, odds ratio 1.58, 1.06-2.36; p = 0.025. The proportion of children and adolescents admitted to an observation ward also decreased from 13 to 9% in 2020, odds ratio 0.52, 0.28-0.96; p = 0.036. Service planners should consider that, during a lockdown, there are likely to be fewer emergency psychiatric presentations. Many children and adolescents with psychiatric emergencies might not receive any service. A focus on developing intensive community care services with outreach capabilities should be prioritised.