Persistent ∆FosB expression limits recurrent seizure activity and provides neuroprotection in the dentate gyrus of APP mice.

Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ∆FosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ∆JunD to interfere with ∆FosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ∆FosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.

Bdellovibrio svalbardensis sp. nov., a newly described predator isolated from Svalbard, Norway.

Identified as a newly described species from a biocrust in Svalbard, Norway (78° 54' 8.27″ N 12° 01' 20.34″ E), isolate PAP01T has different characteristics from any known predatory bacteria. The isolate was vibrio-shaped strain that employed flagellar motility. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolate clustered within the genus Bdellovibrio in the family Bdellovibrionaceae. 16S rRNA gene sequence similarities between strain PAP01T and the type strain (Bdellovibrio bacteriovorus HD100) was 95.7 %. The PAP01T genome has a size of 3.898 Mbp and possesses 3732 genes and a G+C content of 45.7 mol%. The results of genetic and physiological tests indicated the phenotypic differentiation of strain PAP01T from the two other Bdellovibrio species with validly published names. Based on the physiological and phylogenetic data, as well as the prey range spectrum and osmolality sensitivities, isolate PAP01T represents a novel species within the genus Bdellovibrio, for which the name Bdellovibrio svalbardensis sp. nov. is proposed. The type strain is PAP01T (=KCTC 92583T=DSM 115080T).

First quantification and chemical characterization of atmospheric microplastics observed in Seoul, South Korea.

This study is the first report on atmospheric microplastics (MPs) observed in five outdoor environments, including an urban forest, a business center, commercial areas, and a public transportation hub in Seoul, South Korea. Air samples were collected using an active air pump sampler for 24 h in each area only on days without rainfall. All observed microplastics are secondary microplastics, in the form of irregularly-shaped fragments or fibers produced through various degradation processes, rather than being primarily produced like microbeads. The abundance of atmospheric MPs varied depending on the environment (i.e., region, height, and time) from 0.33 to 1.21 MP m-3, with the average number of MPs being 0.72 MP m-3 (standard deviation ± 0.39). MPs in the urban forest was observed to be 27% lower in abundance than that in the urban center which is ∼3 km away. The central business district was observed to have a 25% higher abundance during weekdays than on weekends. Our results show the ubiquity of MPs in various areas from high-rise buildings to forests tens of kilometers away from their direct sources, and a positive correlation between the abundance of MP and human activity. Morphologically, the fragment type (87.4%) predominated over the fiber type (12.6%), and chemically, polypropylene (PP) and polyethylene terephthalate (PET) components accounted for 65% of the total MP. PP polymers were found in all observation sites and contributed to 59% of the total MP fragments. The observed fibrous MPs were mainly composed of PET (72.7%) and PP (18.2%) polymers. Compared to other large cities (Shanghai, Beijing, Paris), Seoul is exposed to low levels of atmospheric MPs and high proportions of PP polymers. This study is limited to atmospheric MPs observed in summer and further investigation of MPs is needed to comprehensively understand the distribution and cycle of MPs based on long-term monitoring of atmospheric MPs.

Lung epithelial and myeloid innate immunity in influenza-associated or COVID-19-associated pulmonary aspergillosis: an observational study.

BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) affect about 15% of critically ill patients with influenza or COVID-19, respectively. These viral-fungal coinfections are difficult to diagnose and are associated with increased mortality, but data on their pathophysiology are scarce. We aimed to explore the role of lung epithelial and myeloid innate immunity in patients with IAPA or CAPA. METHODS: In this observational study, we retrospectively recruited patients who had been admitted to the intensive care unit (ICU) of University Hospitals Leuven, Belgium, requiring non-invasive or invasive ventilation because of severe influenza or COVID-19, with or without aspergillosis, between Jan 1, 2011, and March 31, 2021, whose bronchoalveolar lavage samples were available at the hospital biobank. Additionally, biobanked in vivo tracheobronchial biopsy samples from patients with IAPA or CAPA and invasive Aspergillus tracheobronchitis admitted to ICUs requiring invasive ventilation between the same dates were collected from University Hospitals Leuven, Hospital Network Antwerp (Belgium), and Amiens-Picardie University Hospital (France). We did nCounter gene expression analysis of 755 genes linked to myeloid innate immunity and protein analysis of 47 cytokines, chemokines, and growth factors on the bronchoalveolar lavage samples. Gene expression data were used to infer cell fractions by use of CIBERSORTx, to perform hypergeometric enrichment pathway analysis and gene set enrichment analysis, and to calculate pathway module scores for the IL-1ß, TNF-α, type I IFN, and type II IFN (IFNγ) pathways. We did RNAScope targeting influenza virus or SARS-CoV-2 RNA and GeoMx spatial transcriptomics on the tracheobronchial biopsy samples. FINDINGS: Biobanked bronchoalveolar lavage samples were retrieved from 166 eligible patients, of whom 40 had IAPA, 52 had influenza without aspergillosis, 33 had CAPA, and 41 had COVID-19 without aspergillosis. We did nCounter gene expression analysis on bronchoalveolar lavage samples from 134 patients, protein analysis on samples from 162 patients, and both types of analysis on samples from 130 patients. We performed RNAScope and spatial transcriptomics on the tracheobronchial biopsy samples from two patients with IAPA plus invasive Aspergillus tracheobronchitis and two patients with CAPA plus invasive Aspergillus tracheobronchitis. We observed a downregulation of genes associated with antifungal effector functions in patients with IAPA and, to a lesser extent, in patients with CAPA. We found a downregulated expression of several genes encoding proteins with functions in the opsonisation, recognition, and killing of conidia in patients with IAPA versus influenza only and in patients with CAPA versus COVID-19 only. Several genes related to LC3-associated phagocytosis, autophagy, or both were differentially expressed. Patients with CAPA had significantly lower neutrophil cell fractions than did patients with COVID-19 only. Patients with IAPA or CAPA had downregulated IFNγ signalling compared with patients with influenza only or COVID-19 only, respectively. The concentrations of several fibrosis-related growth factors were significantly elevated in the bronchoalveolar lavage fluid from patients with IAPA versus influenza only and from patients with CAPA versus COVID-19 only. In one patient with CAPA, we visualised an active or very recent SARS-CoV-2 infection disrupting the epithelial barrier, facilitating tissue-invasive aspergillosis. INTERPRETATION: Our results reveal a three-level breach in antifungal immunity in IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytise and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils. The potential of adjuvant IFNγ in the treatment of IAPA and CAPA should be investigated. FUNDING: Research Foundation Flanders, Coronafonds, the Max Planck Society, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, "la Caixa" Foundation, and Horizon 2020.

Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb.

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.

Reproductive Care of Childhood and Adolescent Cancer Survivors: A 12-Year Evaluation.

Background: Reproductive complications for cancer survivors are identified as one of the top unmet needs in the survivorship period. However, current models of cancer care do not routinely incorporate reproductive follow-up for pediatric or adolescent cancer patients. The Kids Cancer Centre has had a one-stop survivorship clinic that includes the attendance of a gynecologist and fertility specialist for the last 12 years. Methodology: To inform the future development of our reproductive survivorship care, we reviewed the reproductive care our survivorship clinic has provided over a 12-year period, specifically reviewing the electronic and patient records to collect information on the demographics of the patients who used the service and their gonadotoxic risk and associated fertility treatment, their documented reproductive needs and concerns, and information provided on preventative reproductive advice and screening. Main Results: Two hundred seventy-eight patients were seen (397 consultations) for advice and management of reproductive issues, including 189 female patients (68.0%). Survivors' median age at follow-up was 25.0 years (range = 6-50), on average 19.2 years from their primary diagnosis (range = 3-46). The reviewed data had five overarching themes (fertility care, hormone dysfunction, sexual dysfunction, fertility-related psychological distress due to reproductive concerns, and preventative health care), although each theme had a number of components. Patients had on average 2.5 reproductive concerns documented per consultation (range 1-5). The three most commonly documented symptoms or concerns at the initial consultation related to fertility status (43.9%), endocrine dysfunction (35.3%), and contraception advice (32.4%). In patients younger than 25 years, documented discussions were predominately about endocrine dysfunction, fertility status, and contraception, while dominant themes for 26-35-year olds were fertility status, reproductive-related health prevention strategies, contraception, and endocrine dysfunction. Survivors 36-45 years of age prioritized fertility status, pregnancy, and contraception. Fertility preservation (FP) (p = 0.05), preventative health strategies (p = 0.001), and contraception advice (p < 0.001) were more commonly discussed by females than males. Conclusion: Young cancer survivors have multiple ongoing reproductive concerns that change over time. Assessing survivors' reproductive potential following cancer treatment is important as it gives patients who have not completed their family planning an opportunity to explore a possible window to FP or Assisted Reproductive Treatment. Our data can assist in informing the model of care for a reproductive survivorship clinic.

Modelling of the Sedative Effects of Propofol in Patients undergoing Spinal Anaesthesia: A Pharmacodynamic Analysis.

Sedation can increase patient comfort during spinal anaesthesia. Understanding the relationship between the propofol effect-site concentration (Ce) and patient sedation level could help clinicians achieve the desired sedation level with minimal side effects. We aimed to model the relationship between the propofol Ce and adequate and deep sedation and also incorporate covariates. Thirty patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. Propofol was administered via an effect-site target-controlled infusion device using the Schnider pharmacokinetic model. The pharmacodynamic models for both adequate sedation [Observer's Assessment of Alertness/Sedation (OAA/S) scores of 3-4] and deep sedation (OAA/S scores of 1-2) were developed using nonlinear mixed-effects modelling. Increments in the propofol Ce were associated with increased depths of sedation. In the basic model, the estimated population Ce50 values for adequate and deep sedation were 0.94 and 1.52 µg/ml, respectively. The inclusion of the patient's age and sensory block level for adequate sedation and of age for deep sedation as covariates significantly improved the basic model by decreasing the objective function's minimum value from 10696.72 to 10677.92 (p = 0.0003). The simulated Ce50 values for adequate sedation in 20-year-old patients with a T12 sensory level and in 80-year-old patients with a T4 level were 1.63 and 0.53 µg/ml, respectively. Both age and sensory block level should be considered for adequate sedation, and the propofol concentration should be reduced for elderly patients with a high spinal block to avoid unnecessarily deep levels of sedation.

Postoperative Pain and Intravenous Patient-Controlled Analgesia-Related Adverse Effects in Young and Elderly Patients: A Retrospective Analysis of 10,575 Patients.

In this retrospective analysis of 10,575 patients who used fentanyl-based intravenous patient-controlled analgesia (IV-PCA) after surgery, we evaluated difference between young and elderly patients on their characteristic of adverse effects.We reviewed the data collected from the patients who were provided IV-PCA for pain control following elective surgery under either general or spinal anesthesia between September 2010 and March 2014. Postoperative pain, incidence of PCA-related adverse effects, and risk factors for the need of rescue analgesics and antiemetics for postoperative 48 hours were analyzed.Pain intensity (numerical rating scale [NRS]) at postoperative 6 to 12 hours (4.68 vs 4.58, P < 0.01) and incidence of nausea or vomiting (23.8% vs 20.6%, P < 0.001) were higher in young patients, while incidence of PCA discontinuation (9.9% vs 11.5%, P < 0.01) and sedation (0.1% vs 0.7%, P < 0.001) was higher in elderly patients. Despite larger fentanyl dose used, a greater proportion of young patients required rescue analgesics (53.8% vs 47.9%, P < 0.001) while addition of ketorolac was effective in reducing postoperative pain. Despite lower incidence of postoperative nausea and vomiting (PONV), a larger proportion of elderly patients required rescue antiemetics (10.1% vs 12.2%, P < 0.001) while addition of ramosetron was effective in reducing PONV.In conclusion, when fentanyl-based IV-PCA is used for postoperative pain control, a larger proportion of young patients may require rescue analgesics while elderly patients may require more rescue antiemetics. The addition of ketorolac or ramosetron to the PCA of young and elderly patients can be effective to prevent rescue analgesics or antiemetics use.