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Widespread Molecular Imprints in the Serum Proteome of COVID-19 Convalescents Uncovering Immune System Sequelae.

Post-COVID-19 sequelae have become an emerging global health issue, but the mechanisms for the sustained susceptibility of convalescents to the sequelae remain poorly understood. Here we report the use of a restricted open-search approach to explore the molecular imprints of SARS-CoV-2 infection left on the proteome of 412 COVID-19 patients and convalescences. A total of 827 non-standard amino acid variations, chemically modified residues as well as post-translational modifications, termed non-coded amino acids (ncAAs), are found spreading over 29,814 sites in patient's serum proteins. Markedly, widespread ncAAs are induced and sustainedly imprinted on the serum proteome predominately perturbing the immunoglobulin-mediated immune response, complement activation and coagulation regulation even 12 months after recovery. Sustained amino acid variations and chemical modifications are found in the complementary‑determining regions (CDRs) of the variable region of immunoglobulin contributing to the interactions between the emerging antibody and antigens; durable chemical amino acid modifications found in the hyper ncAA-modified regions of the constant region of immunoglobulin important for the interaction with the complement and regulatory receptors. In the complement system, inducible ncAAs are memorized in the components essential for the complement activation, amplification cascades and membrane attack processes. Thus, the workflow described in this study can be used to identify the molecular imprints of viral infection at the proteomic scale, particularly the specific antibodies and the immune targets left in COVID-19 patients and convalescents.

Humans

Induced metabolic sequelae of tularemia in the rat: correlation with tissue damage.

Serum and liver zinc concentration, amino acid uptake by liver, seromucoid content, and alpha2-macrofetoprotein production were measured in vaccinated as well as nonimmune rats exposed to either virulent (SCHU S4) or attenuated (LVS) strains of Francisella tularensi. It appears that liver damage (pyogranulomatous lesions) must occur before there is any alteration in the above variables. The presence of bacteria in the liver is not of itself sufficient to lead to the onset of systemic, induced metabolic sequelae (IMS). The occurrence of zinc redistribution in all instances of increased serum protein synthesis may imply a necessary relationship between these two sequelae. Amino acid redistribution does not appear to be linked to serum protein synthesis. An endogenous mediator of systemic IMS can be detected in tularemic rats by injection of the serum of these animals into healthy recipients. The occurrence of zinc redistribution and increased serum protein synthesis in some groups of rats in the absence of amino acids uptake by liver, as well as the apparent differential dose responsiveness of these responses, are suggestive of a multiplicity of endogenous mediators.

Amino Acids

Behavioral sequelae of closed head injury. A quantitative study.

We determined the profile of behavioral disturbance in relation to closed head injury of graded severity. Patients with severe injuries, as defined by duration of coma and the presence of neurological deficit, were differentiated from a group of mildly injured patients by behavioral ratings that reflected cognitive disorganization, emotional withdrawal, and motor retardation. Neurologic measurements of injury related to the severity of behavioral disturbance included hemiparesis, aphasia, and abnormalities on computerized axial tomography. Agitation during the acute phase of injury was also predictive of residual behavioral disturbance. Hemispheric lateralization of the site of greatest injury had no discernible effect on behavioral sequelae.

Adult

Developmental and psychoeducational sequelae of chronic otitis media.

The developmental, psychological, and educational sequelae of chronic otitis media occurring during the first three years of life were investigated in a selected group of children with educational difficulties. One group of children had a history of chronic and severe otitis media, requiring myringotomy after 3 years of age. The control group had infrequent and relatively mild episodes of otitis media and no surgical intervention. Children with chronic and severe otitis media manifested substantial delays in speech and language, auditory processing deficits, disturbances in auditory-visual integration, reading disorders, and poor spelling skills. Early medical and educational intervention for children with a high-risk profile of language delay and severe chronic otitis media is suggested as a possible strategy for preventing the development of a specific learning disability.

Auditory Perception

Neurologic sequelae in the survivors of neonatal intraventricular hemorrhage.

We report our experience with the neurologic sequelae (at a mean follow-up of 24 months) among the 15 surviving infants who have had neonatal intraventricular hemorrhage (IVH) documented by computerized tomographic (CT) brain scan. Neurologically six infants (40%) are normal, six infants (40%) mildly impaired, and three infants (20%) moderate to severely impaired. The neurologic outcome correlated to the degree of hemorrhage seen in the CT scans when IVH was classified into four grades. None of the other neonatal factors examined showed significant correlation with the outcome.

Cerebral Hemorrhage

Experimental cryptorchidism in adult male rats: histological and hormonal sequelae.

Mature male rats were rendered cryptorchid and followed for up to nine weeks during which serial blood specimens were obtained for multiple hormonal analyses; serial testicular samples were obtained as well. In contrast with control animals, cryptorchid rats showed transient rises in FSH which returned to normal at the end of the study; estrogen levels were high in the final weeks. Plasma testosterone levels were unchanged and LH levels changed little. Light and electron microscopic studies of testicular biopsy specimens showed prompt disruption of spermatogenesis which became more extensive with time. Sertoli cells underwent multiple changes including increased lipid storage and phagocytosis of spermatozoa. Comparisons are made between the sequence of hormonal changes and that of histological changes. In addition, questions are raised concerning the ways in which Sertoli cells are affected by experimental cryptorchidism.

Animals

PHACE syndrome: a systematic literature review and illustrative case report of a patient with severe cerebrovascular and neurodevelopmental sequelae.

BACKGROUND: PHACE syndrome is a rare neurocutaneous disorder defined by the association of large segmental infantile hemangiomas of the head and neck with malformations of the posterior fossa, cerebral and cervical arteries, heart, eyes, and ventral midline structures. Although facial hemangiomas are often the presenting feature, the cerebrovascular, neurodevelopmental, and airway manifestations are responsible for the greatest long-term morbidity. METHODS: A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Web of Science, EMBASE, and PsycINFO. After removal of duplicates and screening of 308 records, five studies meeting the inclusion criteria were retained for qualitative synthesis. We additionally present the case of a now 12-year-old girl with PHACE syndrome characterized by a left V1-distribution facial hemangioma, ocular abnormalities, multiple cerebrovascular venous and arterial malformations, neonatal intraventricular hemorrhage with hydrocephalus, and a subsequently diagnosed dural arteriovenous fistula requiring repeated embolization. RESULTS: The five included studies collectively describe epidemiology and early supportive care needs, long-term health outcomes and quality of life into adulthood, airway hemangioma prevalence and management, and the clinical spectrum of infantile hemangiomas with minimal or arrested growth (IH-MAG) as a cutaneous marker of PHACE syndrome. Across studies, cerebrovascular arteriopathy (72-91%) and facial hemangioma residua (> 90%) were the most consistent findings, while progressive arteriopathy, headaches, learning differences, and airway involvement emerged as the principal sources of long-term morbidity. The reported case illustrates an unusually severe cerebrovascular phenotype, including neonatal hemorrhagic hydrocephalus, dural venous sinus thrombosis, and a late dural arteriovenous fistula, culminating in ataxic cerebral palsy and mild intellectual disability. CONCLUSIONS: PHACE syndrome requires a multidisciplinary, lifelong follow-up strategy. The presented case underscores that cerebrovascular complications may evolve over years to decades after the initial diagnosis, reinforcing the need for long-term neuroradiological surveillance even after apparent clinical stability.

Humans

Clinical sequelae of gut microbiome development and disruption in hospitalized preterm infants.

Aberrant preterm infant gut microbiota assembly predisposes to early-life disorders and persistent health problems. Here, we characterize gut microbiome dynamics over the first 3 months of life in 236 preterm infants hospitalized in three neonatal intensive care units using shotgun metagenomics of 2,512 stools and metatranscriptomics of 1,381 stools. Strain tracking, taxonomic and functional profiling, and comprehensive clinical metadata identify Enterobacteriaceae, enterococci, and staphylococci as primarily exploiting available niches to populate the gut microbiome. Clostridioides difficile lineages persist between individuals in single centers, and Staphylococcus epidermidis lineages persist within and, unexpectedly, between centers. Collectively, antibiotic and non-antibiotic medications influence gut microbiome composition to greater extents than maternal or baseline variables. Finally, we identify a persistent low-diversity gut microbiome in neonates who develop necrotizing enterocolitis after day of life 40. Overall, we comprehensively describe gut microbiome dynamics in response to medical interventions in preterm, hospitalized neonates.

Humans

Sequelae of concussion caused by minor head injuries.

Of 145 patients with concussion from minor head injuries admitted to the Royal Victoria Hospital, Belfast, over one year, 49.0 per cent had no symptoms, 38.9 per cent had between 1 and 6 symptoms, and 2.1 per cent had more than 6 symptoms about six weeks after the accident. There was significant correlation between a high symptom-rate at six weeks and positive neurological signs and symptoms at twenty-four hours. Post-concussion symptoms were more frequent in women, in those injured by falls, and in those who blamed their employers or large impersonal organisations for their accidents. The results suggest that both organic and neurotic factors are involved in the pathogenesis of symptoms at six weeks.

Accidents

Ketamine sequelae. Evaluation of the ability of various premedicants to attenuate its psychic actions.

The ability of a number of drugs to abolish the emergence delirium and unpleasant dreams which follow anaesthesia induced with 2 mg/kg ketamine was studied. These included three benzodiazepines, droperidol and 'neurolept' combinations and four commonly-used premedicants. When given intravenously 10 min before induction of anaesthesia flunitrazepam and lorazepam gave best results. In a subsequent study, these two benzodiazepines and diazepam were given intravenously 30-40 min before induction of anaesthesia. There was no doubt that 4 mg lorazepam gave the greatest protection and is worthy of further study in this respect.

Analgesics, Opioid