Prevalence and clinical impact of mono- and co-infections with endemic coronaviruses 229E, OC43, NL63, and HKU-1 during the COVID-19 pandemic.

Introduction: Endemic human coronaviruses (eHCoVs) are found worldwide and usually result in mild to moderate upper respiratory tract infections. They can lead to more severe illnesses such as croup, bronchiolitis, and pneumonia in vulnerable populations. During the coronavirus disease 2019 (COVID-19) pandemic, information on HCoV prevalence and incidence and clinical impact of co-infections of HCoV with SARS-CoV-2 was lacking. Objectives: Thus, this study aimed to determine the prevalence and clinical significance of infections caused by eHCoVs during the COVID-19 pandemic in Bulgaria. Methods: From January 2021 to December 2022, nasopharyngeal swabs of patients with acute upper or lower respiratory tract infections were tested for 17 respiratory viruses using multiplex real-time polymerase chain reaction assays. The clinical data and laboratory parameters of patients infected with respiratory viruses were analysed. Results: Of the 1375 patients screened, 24 (1.7 %) were positive for HCoVs, and 197 (14.3 %) were positive for eight other seasonal respiratory viruses. Five (0.7 %) of 740 patients positive for SARS-CoV-2 were co-infected with eHCoVs. Co-infected patients had a mean C-reactive protein level of 198.5 ± 2.12 mg/mL and a mean oxygen saturation of 82 ± 2.8 mmHg, while those in patients co-infected with SARS-CoV-2 and other respiratory viruses were 61.8 mg/mL and 92.8 ± 4.6 mmHg, respectively (p < 0.05). Pneumonia was diagnosed in 63.3 % of patients with HCoV infection and 6 % of patients positive for other seasonal respiratory viruses (p < 0.05). Patients with SARS-CoV-2 mono-infection stayed in hospital for an average of 5.8 ± 3.7 days, whereas the average hospital stay of patients with eHCoV and SARS-CoV-2 co-infection was 9 ± 1.4 days (p < 0.05). Conclusion: These findings indicate the low prevalence of eHCoVs and low co-infection rate between eHCoVs and SARS-CoV-2 during the COVID-19 pandemic in Bulgaria. Despite their low incidence, such mixed infections can cause severe signs that require oxygen therapy and longer hospital stays, underlining the need for targeted testing of severe COVID-19 cases to identify potential co-infections.

Pontocerebellar hypoplasia type 1 for the neuropediatrician: Genotype-phenotype correlations and diagnostic guidelines based on new cases and overview of the literature.

Pontocerebellar hypoplasia type 1 (PCH1) is a major cause of non-5q spinal muscular atrophy (SMA). We screened 128 SMN1-negative SMA patients from Bulgaria for a frequent mutation -p.G31A in EXOSC3, and performed a literature review of all genetically verified PCH1 cases. Homozygous p.G31A/EXOSC3 mutation was identified in 14 Roma patients, representing three fourths of all our SMN1-negative Roma SMA cases. The phenotype of the p.G31A/EXOSC3 homozygotes was compared to the clinical presentation of all reported to date genetically verified PCH1 cases. Signs of antenatal onset of disease present at birth were common in all PCH1 sub-types except in the homozygous p.D132A/EXOSC3 patients. The PCH1sub-types with early death (between ages 1 day and 17 months), seen in patients with p.G31A/EXOSC3 or SLC25A46 mutations have a SMA type 1-like clinical presentation but with global developmental delay, visual and hearing impairment, with or without microcephaly, nystagmus and optic atrophy. Mutations with milder presentation (homozygous p.D132A/EXOSC3 or VRK1) may display additionally signs of upper motor neuron impairment, dystonia or ataxia and die at age between 5 and 18 years. Other EXOSC3 mutations and EXOSC8 cases are intermediate - SMA type 1-like presentation, spasticity (mostly in EXOSC8) and death between 3 months and 5 years. There is no correlation between neurological onset and duration of life. We add marble-like skin and congenital laryngeal stridor as features of PCH1. We show that imaging signs of cerebellar and pontine hypoplasia may be missing early in infancy. EMG signs of anterior horn neuronopathy may be missing in PCH1 patients with SLC25A46 mutations. Thus, there is considerable phenotypic variability in PCH1, with some cases being more SMA-like, than PCH-like. Detailed clinical evaluation and ethnicity background may guide genetic testing and subsequent genetic counseling.

Identification of quantitative trait loci and candidate genes for an anxiolytic-like response to ethanol in BXD recombinant inbred strains.

Genetic differences in acute behavioral responses to ethanol contribute to the susceptibility to alcohol use disorder and the reduction of anxiety is a commonly reported motive underlying ethanol consumption among alcoholics. Therefore, we studied the genetic variance in anxiolytic-like responses to ethanol across the BXD recombinant inbred (RI) mouse panel using the light-dark transition model of anxiety. Strain-mean genetic mapping and a mixed-model quantitative trait loci (QTL) analysis replicated several previously published QTL for locomotor activity and identified several novel anxiety-related loci. Significant loci included a chromosome 11 saline anxiety-like QTL (Salanq1) and a chromosome 12 locus (Etanq1) influencing the anxiolytic-like response to ethanol. Etanq1 was successfully validated by studies with BXD advanced intercross strains and fine-mapped to a region comprising less than 3.5 Mb. Through integration of genome-wide mRNA expression profiles of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens and ventral midbrain) across the BXD RI panel, we identified high priority candidate genes within Etanq1, the strongest of which was Ninein (Nin), a Gsk3ß-interacting protein that is highly expressed in the brain.