Pfizer BNT 162b2 COVID-19 vaccine-induced fulminant myopericarditis: A case study.

The use of mRNA COVID-19 vaccine can on rare occasions cause life-threatening, fulminant myopericarditis. This case report demonstrates previously reported benefit of early use of venoarterial extracorporeal membrane oxygenation mechanical assistance and supports the use of intravenous highly purified immunoglobulin pharmacotherapy to help achieve a good clinical outcome.

UV-B-induced DNA damage and repair pathways in polar Pseudogymnoascus sp. from the Arctic and Antarctic regions and their effects on growth, pigmentation and conidiogenesis.

Solar radiation regulates most biological activities on Earth. Prolonged exposure to solar UV radiation can cause deleterious effects by inducing two major types of DNA damage, namely, cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts. These lesions may be repaired by the photoreactivation (Phr) and nucleotide excision repair (NER) pathways; however, the principal UV-induced DNA repair pathway is not known in the fungal genus Pseudogymnoascus. In this study, we demonstrated that an unweighted UV-B dosage of 1.6 kJ m-2 d-1 significantly reduced fungal growth rates (by between 22% and 35%) and inhibited conidia production in a 10 d exposure. The comparison of two DNA repair conditions, light or dark, which respectively induced photoreactivation (Phr) and NER, showed that the UV-B-induced CPDs were repaired significantly more rapidly in light than in dark conditions. The expression levels of two DNA repair genes, RAD2 and PHR1 (encoding a protein in NER and Phr respectively), demonstrated that NER rather than Phr was primarily activated for repairing UV-B-induced DNA damage in these Pseudogymnoascus strains. In contrast, Phr was inhibited after exposure to UV-B radiation, suggesting that PHR1 may have other functional roles. We present the first study to examine the capability of the Arctic and Antarctic Pseudogymnoascus sp. to perform photoreactivation and/or NER via RT-qPCR approaches, and also clarify the effects of light on UV-B-induced DNA damage repair in vivo by quantifying cyclobutene pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts. Physiological response data, including relative growth rate, pigmentation and conidia production in these Pseudogymnoascus isolates exposed to UV-B radiation are also presented.

Mixed-mode versus paper surveys for patient-reported outcomes after critical illness: A randomised controlled trial.

OBJECTIVE: The aim of the study was to determine the response rate to a mixed-mode survey using email compared with that to a paper survey in survivors of critical illness. DESIGN: This is a prospective randomised controlled trial. SETTING: The study was conducted at a single-centre quaternary intensive care unit (ICU) in Adelaide, Australia. PARTICIPANTS: Study participants were patients admitted to the ICU for ≥48 h and discharged from the hospital. INTERVENTIONS: The participants were randomised to receive a survey by paper (via mail) or via online (via email, or if a non-email user, via a letter with a website address). Patients who did not respond to the initial survey received a reminder paper survey after 14 days. The survey included quality of life (EuroQol-5D-5L), anxiety and depression (Hospital Anxiety and Depression Scale), and post-traumatic symptom (Impact of Event Scale-Revised) assessment. MAIN OUTCOME MEASURES: Survey response rate, extent of survey completion, clinical outcomes at different time points after discharge, and survey cost analysis were the main outcome measures. Outcomes were stratified based on follow-up time after ICU discharge (3, 6, and 12 months). RESULTS: A total of 239 patients were randomised. The response rate was similar between the groups (mixed-mode: 78% [92/118 patients] vs. paper: 80% [97/121 patients], p = 0.751) and did not differ between time points of follow-up. Incomplete surveys were more prevalent in the paper group (10% vs 18%). The median EuroQol-5D-5L index value was 0.83 [0.71-0.92]. Depressive symptoms were reported by 25% of patients (46/187), anxiety symptoms were reported by 27% (50/187), and probable post-traumatic stress disorder was reported by 14% (25/184). Patient outcomes did not differ between the groups or time points of follow-up. The cost per reply was AU$ 16.60 (mixed-mode) vs AU$ 19.78 (paper). CONCLUSION: The response rate of a mixed-mode survey is similar to that of a paper survey and may provide modest cost savings.

Long term outcomes for Aboriginal and Torres Strait Islander Australians after hospital intensive care.

OBJECTIVES: To assess long term outcomes for Aboriginal and Torres Strait Islander (Indigenous) Australians admitted non-electively to intensive care units (ICUs). DESIGN: Data linkage cohort study; analysis of ICU patient data (Australian and New Zealand Intensive Care Society Adult Patient Database), prospectively collected during 2007-2016. SETTING: All four university-affiliated level 3 ICUs in South Australia. MAIN OUTCOMES: Mortality (in-hospital, and 12 months and 8 years after admission to ICU), by Indigenous status. RESULTS: 2035 of 39 784 non-elective index ICU admissions (5.1%) were of Indigenous Australians, including 1461 of 37 661 patients with South Australian residential postcodes. The median age of Indigenous patients (45 years; IQR, 34-57 years) was lower than for non-Indigenous ICU patients (64 years; IQR, 47-76 years). For patients with South Australian postcodes, unadjusted mortality at discharge and 12 months and 8 years after admission was lower for Indigenous patients; after adjusting for age, sex, diabetes, severity of illness, and diagnostic group, mortality was similar for both groups at discharge (adjusted odds ratio [aOR], 0.95; 95% CI, 0.81-1.10), but greater for Indigenous patients at 12 months (aOR, 1.14; 95% CI, 1.03-1.26) and 8 years (adjusted hazard ratio, 1.23; 95% CI, 1.13-1.35). The number of potential years of life lost was greater for Indigenous patients (median, 24.0; IQR, 15.8-31.8 v 12.5; IQR, 0-22.3), but, referenced to respective population life expectancies, relative survival at 8 years was similar (proportions: Indigenous, 0.78; 95% CI, 0.75-0.80; non-Indigenous, 0.77; 95% CI, 0.76-0.78). CONCLUSIONS: Adjusted long term mortality and median number of potential life years lost are higher for Indigenous than non-Indigenous patients after intensive care in hospital. These differences reflect underlying population survival patterns rather than the effects of ICU admission.

The effect of vertical split-flow patient management on emergency department throughput and efficiency.

BACKGROUND: To address emergency department overcrowding operational research seeks to identify efficient processes to optimize flow of patients through the emergency department. Vertical flow refers to the concept of utilizing and assigning patients virtual beds rather than to an actual physical space within the emergency department to care of low acuity patients. The aim of this study is to evaluate the impact of vertical flow upon emergency department efficiency and patient satisfaction. METHODS: Prospective pre/post-interventional cohort study of all intend-to-treat patients presenting to the emergency department during a two-year period before and after the implementation of a vertical flow model. RESULTS: In total 222,713 patient visits were included in the analysis with 107,217 patients presenting within the pre-intervention and 115,496 in the post-intervention groups. The results of the regression analysis demonstrate an improvement in throughput across the entire ED patient population, decreasing door to departure time by 17 min (95% CI 15-18) despite an increase in patient volume. No statistically significant difference in patient satisfaction scores were found between the pre- and post-intervention. CONCLUSIONS: Initiation of a vertical split flow model was associated with improved ED efficiency.

DNA dependent recruitment of DDX17 and other interacting proteins by the human androgen receptor.

An oligonucleotide-based assay (OBA) was used to identify novel co-factors that can be recruited by the deoxyribonucleic acid (DNA)-bound androgen receptor (AR). Nuclear extracts obtained from LNCaP cells, after incubation with R1881, were incubated with biotinylated oligonucleotides bound to streptavidin coated beads. The oligonucleotides contain 3 copies in tandem of the androgen responsive element ARE1 from the prostate specific antigen (PSA) gene promoter. As control incubation, a scrambled version of the tandem ARE1 was used. Immunoblots of the eluents revealed that the AR was bound to the ARE1 oligonucleotide and to a much lesser extent to the scrambled oligonucleotide. Proteins eluted from the oligonucleotides, were separated on a 5-15% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gradient gel, followed by identification using mass spectrometry. Identified proteins were scored for having one or more of the following known properties: nuclear localization, involved in transcription regulation, involvement in steroid hormone receptor (SHR) function, or specifical involvement in AR function. A total number of 85 nuclear proteins were found in two separate OBAs. Based on peptide counting, we found enrichment of 7 proteins eluted from the ARE1 oligonucleotide, compared to the scrambled oligonucleotide. Taken together with the obtained scores, these proteins are considered putative AR co-factors. One of these proteins, DDX17, is known to be a co-factor for estrogen receptor alpha (ERalpha), but has never been associated with AR function. The results indicate that the ARE oligonucleotide-based assay may allow enrichment of new candidate DNA-bound AR interacting proteins.

A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation.

A novel mutation F826L located within the ligand binding domain (LBD) of the human androgen receptor (AR) was investigated. This mutation was found in a boy with severe penoscrotal hypospadias (classified as 46,XY DSD). The AR mutant F826L appeared to be indistinguishable from the wild-type AR, with respect to ligand binding affinity, transcriptional activation of MMTV-luciferase and ARE2-TATA-luciferase reporter genes, protein level in genital skin fibroblasts (GSFs), and sub-cellular distribution in transfected cells. However, an at least two-fold higher NH2-/COOH-terminal domain interaction was found in luciferase and GST pull-down assays. A two-fold increase was also observed for TIF2 (transcription intermediary factor 2) co-activation of the AR F826L COOH-terminal domain. This increase could not be explained by a higher stability of the mutant protein, which was within wild-type range. Repression of transactivation by the nuclear receptor co-repressor (N-CoR) was not affected by the AR F826L mutation. The observed properties of AR F826L would be in agreement with an increased activity rather than with a partial defective AR transcriptional activation. It is concluded that the penoscrotal hypospadias in the present case is caused by an as yet unknown mechanism, which still may involve the mutant AR.

Phosphorylation of androgen receptor isoforms.

Phosphorylation of the human AR (androgen receptor) is directly correlated with the appearance of at least three AR isoforms on an SDS/polyacrylamide gel. However, it is still not clear to what extent phosphorylation is involved in the occurrence of isoforms, which sites are phosphorylated and what are the functions of these phosphosites. The human AR was expressed in COS-1 cells and AR phosphorylation was studied further by mutational analyses and by using reversed-phase HPLC and MS. The reversed-phase HPLC elution pattern of the three isoforms revealed that Ser-650 was phosphorylated constitutively. After de novo synthesis, only Ser-650 was phosphorylated in the smallest isoform of 110 kDa and both Ser-650 and Ser-94 were phosphorylated in the second isoform of 112 kDa. The hormone-induced 114 kDa isoform shows an overall increase in phosphorylation of all the isolated peptides. The activities of the Ser-Ala substitution mutant S650A (Ser-650-->Ala) was found to be identical with wild-type AR activation in four different cell lines and three different functional analyses, e.g. transactivation, N- and C-terminal-domain interaction and co-activation by transcriptional intermediary factor 2. This was also found for mutants S94A and S515A with respect to transactivation. However, the S515A mutation, which should eliminate phosphorylation of the potential mitogen-activated protein kinase site, Ser-515, resulted in an unphosphorylated form of the peptide containing Ser-650. This suggests that Ser-515 can modulate phosphorylation at another site. The present study shows that the AR isoform pattern from AR de novo synthesis is directly linked to differential phosphorylation of a distinct set of sites. After mutagenesis of these sites, no major change in functional activity of the AR was observed.