Spike N354 glycosylation augments SARS-CoV-2 fitness for human adaptation through multiple mechanisms (preprint)

Selective pressures have given rise to a number of SARS-CoV-2 variants during the prolonged course of the COVID-19 pandemic. Recently evolved variants differ from ancestors in additional glycosylation within the spike protein receptor-binding domain (RBD). Details of how the acquisition of glycosylation impacts viral fitness and human adaptation are not clearly understood. Here, we dissected the role of N354-linked glycosylation, acquired by BA.2.86 sub-lineages, as a RBD conformational control element in attenuating viral infectivity. The reduced infectivity could be recovered in the presence of heparin sulfate, which targets the N354 pocket to ease restrictions of conformational transition resulting in a RBD-up state, thereby conferring an adjustable infectivity. Furthermore, N354 glycosylation improved spike cleavage and cell-cell fusion, and in particular escaped one subset of ADCC antibodies. Together with reduced immunogenicity in hybrid immunity background, these indicate a single spike amino acid glycosylation event provides selective advantage in humans through multiple mechanisms.

Exploring Emotions Related to the COVID-19 Pandemic through Death Education: A Qualitative Study in Italian Primary Schools (preprint)

Background: The Covid-19 pandemic has globally impacted the lives of individuals, families, and children. In Italy, measures such as lockdowns and distance learning were implemented in schools, which affected the mental health of children and families. Methods: This article employs qualitative methodology to explore the experiences of children, parents, and teachers during the pandemic and lockdown, as well as the implementation of a death education project aimed at primary school children to help them process emotions and losses experienced during this period. Results: Distance learning posed challenges to the learning process and exacerbated social inequalities. Children suffered from limited social contact with friends and experienced negative emotions, including anger, fear, and concern for the health of their loved ones. The death education project provided a safe space for emotional expression and facilitated the acquisition of coping strategies. Open communication between adults and children about illness and death proved effective in mitigating the psychological impacts of loss and preventing traumatic bereavement. Conclusions: The findings highlight the utility of death education in enhancing children's ability to express their emotions and approach the topic of death morefrankly.

Biperiden for prevention of post-traumatic epilepsy: A protocol of a double-blinded placebo-controlled randomized clinical trial (BIPERIDEN trial).

BACKGROUND: Traumatic brain injury (TBI) is one of the most important causes of acquired structural epilepsy, post-traumatic epilepsy (PTE), however, efficient preventative measures and treatment are still not available to patients. Preclinical studies indicated biperiden, an anticholinergic drug, as a potential drug to modify the epileptogenic process. The main objective of this clinical trial is to evaluate the efficacy of biperiden as an antiepileptogenic agent in patients that suffered TBI. METHODS: This prospective multicenter (n = 10) interventional study will include 312 adult patients admitted to emergency care units with a diagnosis of moderate or severe TBI. Following inclusion and exclusion criteria, patients will be randomized, using block randomization, to receive double-blind treatment with placebo or biperiden for 10 days. Follow-up will occur at specific time windows up to 2 years. Main outcomes are incidence of PTE after TBI and occurrence of severe adverse events. Other outcomes include exploratory investigation of factors that might have benefits for the treatment or might influence its results, such as genetic background, clinical progression, electroencephalographic abnormalities, health-related quality of life and neuropsychological status. Analyses will be conducted following the safety, intention-to-treat and efficacy concepts. DISCUSSION: We hypothesize that biperiden treatment will be effective to prevent or mitigate the development of post-traumatic epilepsy in TBI patients. Other health measures from this population also may benefit from treatment with biperiden. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04945213. Registered on June 30, 2021.

Microbiome Mediates Development of PTSD and Resilience (preprint)

Identification of youth at risk for post-traumatic pathology is critical for public health, medicine, and social policy but research has not yet succeeded in pinpointing biomarkers that can distinguish the post-traumatic from the resilient profile in contexts of trauma. As trauma alters the microbiome with lasting effects on the host, the current longitudinal, multi-measure, cross-species study sought to outline the microbial signature of post-traumatic stress disorder (PTSD). We followed a unique trauma-exposed cohort for 15 years, from early childhood to adolescence, repeatedly assessing post-traumatic symptomatology. Gut microbiome composition and diversity characterized post-traumatic pathology, distinguished youth with PTSD from resilient individuals, and mediated the continuity of post-traumatic disorder. Mother-child microbial synchrony was reduced in cases of PTSD, suggesting that diminished microbial concordance among family members may index susceptibility to post-traumatic illness. Germ-free mice transplanted with PTSD microbiomes compared with those receiving resilient microbiomes exhibited anxious behavior. Our findings provide causative evidence that the microbial trauma profile is at least partially responsible for the trauma-related phenotype and highlight microbial underpinnings of resilience. Our results suggest that the microbial ecology may serve as additional biological memory of early life stress and underscore the potential for microbiome-related diagnosis and treatment following trauma exposure.

Association of COVID-19 with risks of hospitalization and mortality from other disorders post-infection: A study of the UK Biobank (preprint)

ObjectiveTo study whether COVID-19 infection may be associated with increased hospitalization and mortality from other diseases. DesignCohort study. SettingThe UK Biobank. ParticipantsAll subjects in the UK Biobank with available hospitalization records and alive as of 31-Jan-2020 (N= 412,096; age 50-87). Main outcome measuresWe investigated associations of COVID-19 with hospitalization and mortality due to different diseases post-infection. We conducted a comprehensive survey on disorders from all systems (up to 135 disease categories). Multivariable Cox and Poisson regression was conducted controlling for main confounders. For sensitivity analysis, we also conducted separate analysis for new-onset and recurrent cases, and other analysis such as the prior event rate adjustment(PERR) approach to minimize effects of unmeasured confounders. We also performed association analyses stratified by vaccination status. Time-dependent effects on subsequent hospitalization and mortality were also tested. ResultsCompared to individuals with no known history of COVID-19, those with severe COVID-19 (requiring hospitalization) exhibited higher hazards of hospitalization and/or mortality due to multiple disorders (median follow-up=608 days), including disorders of respiratory, cardiovascular, neurological, gastrointestinal, genitourinary and musculoskeletal systems. Increased hazards of hospitalizations and/or mortality were also observed for injuries due to fractures, various infections and other non-specific symptoms. These results remained largely consistent after sensitivity analyses. Severe COVID-19 was also associated with increased all-cause mortality (HR=14.700, 95% CI: 13.835-15.619). Mild (non-hospitalized) COVID-19 was associated with modestly increased risk of all-cause mortality (HR=1.237, 95% CI 1.037-1.476) and mortality from neurocognitive disorders, as well as hospital admission from a few disorders such as aspiration pneumonitis, musculoskeletal pain and other general signs/symptoms. All-cause mortalities and hospitalizations from other disorders post-infection were generally higher in the pre-vaccination era. The deleterious effect of COVID-19 was observed to wane over time, with maximum HR in the initial phase. ConclusionsIn conclusion, this study revealed increased risk of hospitalization and mortality from a wide variety of pulmonary and extra-pulmonary diseases after COVID-19, especially for severe infections. Mild disease was also associated with increased all-cause mortality. Causality however cannot be established due to observational nature of the study. Further studies are required to replicate our findings.