Carbon monoxide-releasing molecules (CORMs) are being developed with the ultimate goal of safely utilizing the therapeutic potential of CO clinically, including applications in antimicrobial therapy. ...Hemes are generally considered the prime targets of CO and CORMs, so we tested this hypothesis using heme-deficient bacteria, applying cellular, transcriptomic, and biochemical tools.
CORM-3 Ru(CO)3Cl(glycinate) readily penetrated Escherichia coli hemA bacteria and was inhibitory to these and Lactococcus lactis, even though they lack all detectable hemes. Transcriptomic analyses, coupled with mathematical modeling of transcription factor activities, revealed that the response to CORM-3 in hemA bacteria is multifaceted but characterized by markedly elevated expression of iron acquisition and utilization mechanisms, global stress responses, and zinc management processes. Cell membranes are disturbed by CORM-3.
This work has demonstrated for the first time that CORM-3 (and to a lesser extent its inactivated counterpart) has multiple cellular targets other than hemes. A full understanding of the actions of CORMs is vital to understand their toxic effects.
This work has furthered our understanding of the key targets of CORM-3 in bacteria and raises the possibility that the widely reported antimicrobial effects cannot be attributed to classical biochemical targets of CO. This is a vital step in exploiting the potential, already demonstrated, for using optimized CORMs in antimicrobial therapy.
The oral microbiota has been implicated in the pathogenesis of rheumatoid arthritis through activation of mucosal immunity. This study tested for associations between oral health, microbial ...communities and juvenile idiopathic arthritis (JIA).
A cross-sectional exploratory study of subjects aged 10-18 years with oligoarticular, extended oligoarticular and polyarticular JIA was conducted. Control groups included pediatric dental clinic patients and healthy volunteers. The primary aim was to test for an association between dental health indices and JIA; the secondary aim was to characterize the microbial profile of supragingival plaque using 16S rRNA gene sequencing.
The study included 85 patients with JIA, 62 dental patients and 11 healthy child controls. JIA patients overall had significantly more gingival inflammation compared to dental patients, as evidenced by bleeding on probing of the gingiva, the most specific sign of active inflammation (p = 0.02). Overall, however, there was a trend towards better dental hygiene in the JIA patients compared to dental patients, based on indices for plaque, decay, and periodontitis. In the JIA patients, plaque microbiota analysis revealed bacteria belonging to genera Haemophilus or Kingella elevated, and Corynebacterium underrepresented. In poly JIA, bacteria belonging to the genus Porphyromonas was overrepresented and Prevotella was underrepresented.
Increased gingival inflammation in JIA was independent of general oral health, and thus cannot be attributed to poor dental hygiene secondary to disability. The variation of microbial profile in JIA patients could indicate a possible link between gingivitis and synovial inflammation.
Waste electrical and electronic equipment (WEEE) are a source of both hazardous and valuable materials that must be segregated for treatment. Previous studies addressing the use of handheld X-Ray ...fluorescence (h-XRF) as a sorting tool for WEEE plastics through the identification of hazardous components include plastics from mixed WEEE streams, processed material (shredded or treated plastics) and low number of samples not allowing to consider their findings for application on an industrial scale. Thus, further research is needed to establish scalable robust methods for sorting this material. We describe a study carried out on whole flat panel display equipment (FPD) plastic casings using h-XRF for the detection of total bromine (Br) and antimony (Sb) as tracers for Brominated Flame Retardants (BFRs) and Sb2O3 additives. The aim being to characterize the targeted material and to define the optimal analysis conditions to meet large scale throughputs. A ring trial exercise comprising 100 samples was conducted to evaluate the validity of the measurements. Results indicate that: 1) the use of h-XRF under the conditions determined in this study offers a valid technique to screen total Br and Sb in whole FPD casings at industrial scale with low uncertainty, 2) Br and Sb are found to be homogeneously distributed within the casing, 3) an optimal h-XRF analysis time of 10 seconds is suitable from both accuracy and practical implementation for LOD<Br≤ 830 mg kg−1 and LOD<Sb≤8400 mg kg−1, and 4) the presence of dust deposited on the casings was excluded as a factor affecting h-XRF results. To our knowledge this is the first evaluation of optimal sorting conditions for whole display casings using h-XRF, within a manual dismantling process.
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Purpose
The goal was to identify molecular imaging probes that would enter the brain, selectively bind to Parkinson’s disease (PD) pathology, and be detectable with one or more imaging modalities.
...Procedure
A library of organic compounds was screened for the ability to bind hallmark pathology in human Parkinson’s and Alzheimer’s disease tissue, alpha-synuclein oligomers and inclusions in two cell culture models, and alpha-synuclein aggregates in cortical neurons of a transgenic mouse model. Finally, compounds were tested for blood–brain barrier permeability using intravital microscopy.
Results
Several lead compounds were identified that bound the human PD pathology, and some showed selectivity over Alzheimer’s pathology. The cell culture models and transgenic mouse models that exhibit alpha-synuclein aggregation did not prove predictive for ligand binding. The compounds had favorable physicochemical properties, and several were brain permeable.
Conclusions
Future experiments will focus on more extensive evaluation of the lead compounds as PET ligands for clinical imaging of PD pathology.
Objective
The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age‐at‐onset of Parkinson's disease.
Methods
We performed the ...first genomewide association study of penetrance and age‐at‐onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non‐cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age‐at‐onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age‐at‐onset in LRRK2 mutation carriers.
Results
A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E‐08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co‐immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E‐07; age‐at‐onset top variant: p value = 9.3E‐07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age‐at‐onset.
Interpretation
This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82–94
Abstract
Background
Antibiotic prescribing varies among providers, contributing to antibiotic resistance and adverse drug reactions.
Objective. To evaluate variation in antibiotic prescribing between ...pediatric and nonpediatric providers for common upper respiratory illnesses.
Methods
Patient encounters for children aged <18 years from a regional healthcare system were identified. Electronic medical records from 2011 to 2016 were extracted for diagnoses of upper respiratory infection (URI), pharyngitis, acute otitis media (AOM), and sinusitis. Encounters with competing medical diagnoses, recent hospitalization, and antibiotic prescriptions within 30 days were excluded. Adherence to antibiotic guidelines was assessed by provider training (pediatric, nonpediatric physicians, and advance practice providers APP). Additional factors assessed included clinic or urgent care setting, calendar year, and patient’s age, gender, insurance status, and number of sick visits in the prior year.
Results
Across 6 years, 141,361 visits were examined: 43,914 for URI, 43,701 for pharyngitis, 43,925 for AOM, and 9,821 for sinusitis. Pediatricians were more likely than APPs and nonpediatric providers to have guideline-concordant prescribing for pharyngitis (pediatricians 66.7 (54.5, 77.0)%, nonpediatricians 49.1 (36.3, 62.0)%, APPs 52.2(39.4, 64.7)%, P < 0.0001) and sinusitis (pediatricians 70.8(53.8, 83.4)%, nonpediatricians 63.3(46.8, 77.2)%, APPs 62.1(45.1, 76.5)%, P = 0.48) and to withhold antibiotics for URI than APPs and nonpediatric providers (pediatricians 86.6(81.2, 90.6)%, nonpediatricians 80.8(73.0, 86.8)%, APPs 76.8(68.4, 83.5)%, P < 0.0001). Pediatricians were less likely to prescribe antibiotics for pharyngitis without a positive Group A Streptococcus test than APPs and nonpediatric providers (pediatricians 15.1(10.4, 21.6)%, nonpediatricians 29.4(20.8, 39.6)%, APPs 27.2(19.3, 36.9)%, P < 0.0001). First-line antibiotic prescribing for pharyngitis and AOM did not differ between provider specialties. A trend toward more guideline-concordant prescribing was seen for pharyngitis and sinusitis over the study period.
Conclusion
Pediatricians were more likely to adhere to guidelines for pediatric acute respiratory infections. Pediatric antibiotic stewardship efforts should also target non-pediatricians.
Disclosures
All authors: No reported disclosures.
A novel α7 nAChR agonist, 4-(5-methyloxazolo4,5-bpyridin-2-yl)-1,4-diazabicyclo3.2.2nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with ...psychiatric or neurological conditions including schizophrenia and Alzheimer’s disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that α7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.
Children account for a substantial proportion of cases and deaths during Ebola virus disease outbreaks. We aimed to evaluate the safety and immunogenicity of a booster dose of the Ad26.ZEBOV vaccine ...in children who had been vaccinated with a two-dose regimen comprising Ad26.ZEBOV as dose one and MVA-BN-Filo as dose two.
We conducted an open-label, non-randomised, phase 2 trial at one clinic in Kambia Town, Sierra Leone. Healthy children, excluding pregnant or breastfeeding girls, who had received the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen in a previous study, and were aged 1–11 years at the time of their first vaccine dose, received an intramuscular injection of Ad26.ZEBOV (5 × 1010 viral particles) and were followed up for 28 days. Primary outcomes were safety (measured by adverse events) and immunogenicity (measured by Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration) of the booster vaccine dose. Safety was assessed in all participants who received the booster vaccination; immunogenicity was assessed in all participants who received the booster vaccination, had at least one evaluable sample after the booster, and had no major protocol deviations that could have influenced the immune response. This trial is registered with ClinicalTrials.gov, NCT04711356.
Between July 8 and Aug 18, 2021, 58 children were assessed for eligibility and 50 (27 aged 4–7 years and 23 aged 9–15 years) were enrolled and received an Ad26.ZEBOV booster vaccination, more than 3 years after receiving dose one of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen. The booster was well tolerated. The most common solicited local adverse event during the 7 days after vaccination was injection site pain, reported in 18 (36%, 95% CI 23–51) of 50 participants. The most common solicited systemic adverse event during the 7 days after vaccination was headache, reported in 11 (22%, 12–36) of 50 participants. Malaria was the most common unsolicited adverse event during the 28 days after vaccination, reported in 25 (50%, 36–64) of 50 participants. No serious adverse events were observed during the study period. 7 days after vaccination, the Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration was 28 561 ELISA units per mL (95% CI 20 255–40 272), which was 44 times higher than the geometric mean concentration before the booster dose. 21 days after vaccination, the geometric mean concentration reached 64 690 ELISA units per mL (95% CI 48 356–86 541), which was 101 times higher than the geometric mean concentration before the booster dose.
A booster dose of Ad26.ZEBOV in children who had received the two-dose Ad26.ZEBOV and MVA-BN-Filo vaccine regimen more than 3 years earlier was well tolerated and induced a rapid and robust increase in binding antibodies against Ebola virus. These findings could inform Ebola vaccination strategies in paediatric populations.
Innovative Medicines Initiative 2 Joint Undertaking.
For the French translation of the abstract see Supplementary Materials section.
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