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| 3. |
- Sen, P, et al.
(author)
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Vaccine hesitancy decreases in rheumatic diseases, long-term concerns remain in myositis: a comparative analysis of the COVAD surveys
- 2023
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In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 62:10, s. 3291-3301
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Journal article (peer-reviewed)abstract
- ObjectiveCOVID-19 vaccines have a favorable safety profile in patients with autoimmune rheumatic diseases (AIRDs) such as idiopathic inflammatory myopathies (IIMs); however, hesitancy continues to persist among these patients. Therefore, we studied the prevalence, predictors and reasons for hesitancy in patients with IIMs, other AIRDs, non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs), using data from the two international COVID-19 Vaccination in Autoimmune Diseases (COVAD) e-surveys.MethodsThe first and second COVAD patient self-reported e-surveys were circulated from March to December 2021, and February to June 2022 (ongoing). We collected data on demographics, comorbidities, COVID-19 infection and vaccination history, reasons for hesitancy, and patient reported outcomes. Predictors of hesitancy were analysed using regression models in different groups.ResultsWe analysed data from 18 882 (COVAD-1) and 7666 (COVAD-2) respondents. Reassuringly, hesitancy decreased from 2021 (16.5%) to 2022 (5.1%) (OR: 0.26; 95% CI: 0.24, 0.30, P < 0.001). However, concerns/fear over long-term safety had increased (OR: 3.6; 95% CI: 2.9, 4.6, P < 0.01). We noted with concern greater skepticism over vaccine science among patients with IIMs than AIRDs (OR: 1.8; 95% CI: 1.08, 3.2, P = 0.023) and HCs (OR: 4; 95% CI: 1.9, 8.1, P < 0.001), as well as more long-term safety concerns/fear (IIMs vs AIRDs – OR: 1.9; 95% CI: 1.2, 2.9, P = 0.001; IIMs vs HCs – OR: 5.4 95% CI: 3, 9.6, P < 0.001). Caucasians [OR 4.2 (1.7–10.3)] were likely to be more hesitant, while those with better PROMIS physical health score were less hesitant [OR 0.9 (0.8–0.97)].ConclusionVaccine hesitancy has decreased from 2021 to 2022, long-term safety concerns remain among patients with IIMs, particularly in Caucasians and those with poor physical function.
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| 4. |
- Martinez, K., et al.
(author)
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Uncertainty assessment of polychlorinated dibenzo-p-dioxins and dibenzofuran and dioxin-like polychlorinated biphenyl analysis in stationary source sample emissions in accordance with the impending European standard EN-1948 using fly ashes
- 2009
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In: Journal of Chromatography A. - : Elsevier BV. - 0021-9673 .- 1873-3778. ; 1216:31, s. 5888-5894
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Journal article (peer-reviewed)abstract
- The analysis of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) present in stack gas emissions and solid residues from incinerators will be mandatory in the foreseeable future. European standard EN-1948 is in the process of being updated through the addition of a new Part 4 related to the analysis of the 12 dl-PCBs. Therefore, either a comprehensive and reliable method capable of analyzing all of these 29 compounds (12 dl-PCBs and 17 2,3,7,8-PCDD/Fs) needs to be developed, or the existing PCDD/F analytical procedure must be adapted to include the dl-PCBs. This study has taken the latter approach of modifying PCDD/F methodology and in particular the fractionation step, by isolating dioxins and dl-PCBs into separate fractions ready for high resolution gas chromatography coupled to high resolution mass spectrometry (HRGC/HRMS) analysis. Results obtained from the analysis of Certified Reference Materials (CRM-490 and CRM-615) and fly ashes from the European Committee for Standardization (CEN) intercalibration study demonstrated that the proposed methodology is appropriate to determine the dl-PCBs in accordance with the impending European standard EN-1948. Uncertainty values obtained during the validation of the analytical methodology were 13% total I-TEQ (international Toxic Equivalent) for PCDD/Fs and 31% total WHO-TEQ (World Health Organization Toxic Equivalent) in the case of dl-PCBs. In addition, 'real' samples such as emissions and fly ashes were successfully analyzed following the proposed analytical method. (C) 2009 Elsevier B.V. All rights reserved.
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| 5. |
- Arber, C., et al.
(author)
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Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
- 2019
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In: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 1:1
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Journal article (peer-reviewed)abstract
- Mutations in presenilin-1 (PSEN1), encoding the catalytic subunit of the amyloid precursor protein-processing enzyme gamma-secretase, cause familial Alzheimer's disease. However, the mechanism of disease is yet to be fully understood and it remains contentious whether mutations exert their effects predominantly through gain or loss of function. To address this question, we generated an isogenic allelic series for the PSEN1 mutation intron 4 deletion; represented by control, heterozygous and homozygous mutant induced pluripotent stem cells in addition to a presenilin-1 knockout line. Induced pluripotent stem cell-derived cortical neurons reveal reduced, yet detectable amyloid-beta levels in the presenilin-1 knockout line, and a mutant gene dosage-dependent defect in amyloid precursor protein processing in PSEN1 intron 4 deletion lines, consistent with reduced processivity of gamma-secretase. The different effects of presenilin-1 knockout and the PSEN1 intron 4 deletion mutation on amyloid precursor protein-C99 fragment accumulation, nicastrin maturation and amyloid-beta peptide generation support distinct consequences of familial Alzheimer's disease-associated mutations and knockout of presenilin-1 on the function of gamma-secretase.
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| 6. |
- James, Bethan L., et al.
(author)
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CLASSY. II. A Technical Overview of the COS Legacy Archive Spectroscopic Survey
- 2022
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In: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 262:2
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Journal article (peer-reviewed)abstract
- The COS Legacy Archive Spectroscopic SurveY (CLASSY) is designed to provide the community with a spectral atlas of 45 nearby star-forming galaxies that were chosen to cover similar properties to those seen at high z (z > 6). The prime high-level science product of CLASSY is accurately coadded UV spectra, ranging from ∼1000 to 2000 Å, derived from a combination of archival and new data obtained with HST's Cosmic Origins Spectrograph (COS). This paper details the multistage technical processes of creating this prime data product and the methodologies involved in extracting, reducing, aligning, and coadding far-ultraviolet and near-ultraviolet (NUV) spectra. We provide guidelines on how to successfully utilize COS observations of extended sources, despite COS being optimized for point sources, and best-practice recommendations for the coaddition of UV spectra in general. Moreover, we discuss the effects of our reduction and coaddition techniques in the scientific application of the CLASSY data. In particular, we find that accurately accounting for flux calibration offsets can affect the derived properties of the stellar populations, while customized extractions of NUV spectra for extended sources are essential for correctly diagnosing the metallicity of galaxies via C iii] nebular emission. Despite changes in spectral resolution of up to ∼25% between individual data sets (due to changes in the COS line-spread function), no adverse affects were observed on the difference in velocity width and outflow velocities of isolated absorption lines when measured in the final combined data products, owing in part to our signal-to-noise regime of S/N < 20.
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| 7. |
- Garcia-Reitboeck, P., et al.
(author)
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Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis
- 2018
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 24:9, s. 2300-2311
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Journal article (peer-reviewed)abstract
- Dysfunction of microglia, the brain's immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals.
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| 9. |
- Bedada, W, et al.
(author)
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Effects of Khat (Catha edulis) use on catalytic activities of major drug-metabolizing cytochrome P450 enzymes and implication of pharmacogenetic variations
- 2018
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 12726-
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Journal article (peer-reviewed)abstract
- In a one-way cross-over study, we investigated the effect of Khat, a natural amphetamine-like psychostimulant plant, on catalytic activities of five major drug-metabolizing cytochrome P450 (CYP) enzymes. After a one-week Khat abstinence, 63 Ethiopian male volunteers were phenotyped using cocktail probe drugs (caffeine, losartan, dextromethorphan, omeprazole). Phenotyping was repeated after a one-week daily use of 400 g fresh Khat leaves. Genotyping for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5 were done. Urinary cathinone and phenylpropanolamine, and plasma probe drugs and metabolites concentrations were quantified using LC-MS/MS. Effect of Khat on enzyme activities was evaluated by comparing caffeine/paraxanthine (CYP1A2), losartan/losartan carboxylic acid (CYP2C9), omeprazole/5-hydroxyomeprazole (CYP2C19), dextromethorphan/dextrorphan (CYP2D6) and dextromethorphan/3-methoxymorphinan (CYP3A4) metabolic ratios (MR) before and after Khat use. Wilcoxon-matched-pair-test indicated a significant increase in median CYP2D6 MR (41%, p < 0.0001), and a marginal increase in CYP3A4 and CYP2C19 MR by Khat. Repeated measure ANOVA indicated the impact of CYP1A2 and CYP2C19 genotype on Khat-CYP enzyme interactions. The median MR increased by 35% in CYP1A2*1/*1 (p = 0.07) and by 40% in carriers of defective CYP2C19 alleles (p = 0.03). Urinary log cathinone/phenylpropanolamine ratios significantly correlated with CYP2D6 genotype (p = 0.004) and CYP2D6 MR (P = 0.025). Khat significantly inhibits CYP2D6, marginally inhibits CYP3A4, and genotype-dependently inhibit CYP2C19 and CYP1A2 enzyme activities.
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| 10. |
- Berg, Danielle A., et al.
(author)
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The COS Legacy Archive Spectroscopy Survey (CLASSY) Treasury Atlas
- 2022
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In: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 261:2
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Journal article (peer-reviewed)abstract
- Far-ultraviolet (FUV; ∼1200–2000 Å) spectra are fundamental to our understanding of star-forming galaxies, providing a unique window on massive stellar populations, chemical evolution, feedback processes, and reionization. The launch of the James Webb Space Telescope will soon usher in a new era, pushing the UV spectroscopic frontier to higher redshifts than ever before; however, its success hinges on a comprehensive understanding of the massive star populations and gas conditions that power the observed UV spectral features. This requires a level of detail that is only possible with a combination of ample wavelength coverage, signal-to-noise, spectral-resolution, and sample diversity that has not yet been achieved by any FUV spectral database. We present the Cosmic Origins Spectrograph Legacy Spectroscopic Survey (CLASSY) treasury and its first high-level science product, the CLASSY atlas. CLASSY builds on the Hubble Space Telescope (HST) archive to construct the first high-quality (S/N1500 Å ≳ 5/resel), high-resolution (R ∼ 15,000) FUV spectral database of 45 nearby (0.002 < z < 0.182) star-forming galaxies. The CLASSY atlas, available to the public via the CLASSY website, is the result of optimally extracting and coadding 170 archival+new spectra from 312 orbits of HST observations. The CLASSY sample covers a broad range of properties including stellar mass (6.2 < log M⋆(M⊙) < 10.1), star formation rate (−2.0 < log SFR (M⊙ yr−1) < +1.6), direct gas-phase metallicity (7.0 < 12+log(O/H) < 8.8), ionization (0.5 < O32 < 38.0), reddening (0.02 < E(B − V) < 0.67), and nebular density (10 < ne (cm−3) < 1120). CLASSY is biased to UV-bright star-forming galaxies, resulting in a sample that is consistent with the z ∼ 0 mass–metallicity relationship, but is offset to higher star formation rates by roughly 2 dex, similar to z ≳ 2 galaxies. This unique set of properties makes the CLASSY atlas the benchmark training set for star-forming galaxies across cosmic time.
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| 15. |
- Matthee, Jorryt, et al.
(author)
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(Re)Solving reionization with Lyα : how bright Lyα Emitters account for the z ≈ 2–8 cosmic ionizing background
- 2022
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 512:4, s. 5960-5977
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Journal article (peer-reviewed)abstract
- The cosmic ionizing emissivity from star-forming galaxies has long been anchored to UV luminosity functions. Here, we introduce an emissivity framework based on Lyα emitters (LAEs), which naturally hones in on the subset of galaxies responsible for the ionizing background due to the intimate connection between production and escape of Lyα and LyC photons. Using constraints on the escape fractions of bright LAEs (LLyα > 0.2L*) at z ≈ 2 obtained from resolved Lyα profiles, and arguing for their redshift-invariance, we show that: (i) quasars and LAEs together reproduce the relatively flat emissivity at z ≈ 2–6, which is non-trivial given the strong evolution in both the star formation density and quasar number density at these epochs and (ii) LAEs produce late and rapid reionization between z ≈ 6−9 under plausible assumptions. Within this framework, the >10 × rise in the UV population-averaged fesc between z ≈ 3–7 naturally arises due to the same phenomena that drive the growing LAE fraction with redshift. Generally, a LAE dominated emissivity yields a peak in the distribution of the ionizing budget with UV luminosity as reported in latest simulations. Using our adopted parameters (fesc=50 per cent, ξion = 1025.9 Hz erg−1 for half the bright LAEs), a highly ionizing minority of galaxies with MUV < −17 accounts for the entire ionizing budget from star-forming galaxies. Rapid flashes of LyC from such rare galaxies produce a ‘disco’ ionizing background. We conclude proposing tests to further develop our suggested Lyα-anchored formalism.
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| 16. |
- Mingozzi, Matilde, et al.
(author)
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CLASSY IV. Exploring UV Diagnostics of the Interstellar Medium in Local High-z Analogs at the Dawn of the JWST Era
- 2022
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 939:2
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Journal article (peer-reviewed)abstract
- The Cosmic Origins Spectrograph (COS) Legacy Archive Spectroscopic SurveY (CLASSY) provides the first high-resolution spectral catalog of 45 local high-z analogs in the ultraviolet (UV; 1200–2000 Å) to investigate their stellar and gas properties. Here we present a toolkit of UV interstellar medium (ISM) diagnostics, analyzing the main emission lines of CLASSY spectra (N iv] λλ1483,87, C iv λλ1548,51, He iiλ1640, O iii]λλ1661,6, Si iii] λλ1883,92, C iii] λ1907,9). Specifically, our aim is to provide accurate diagnostics for the reddening E(B − V), electron density ne, electron temperature Te, metallicity 12+log(O/H), and ionization parameter log(U), taking the different ISM ionization zones into account. We calibrate our UV toolkit using well-known optical diagnostics, analyzing archival optical spectra for all CLASSY targets. We find that UV density diagnostics estimate ne values that are ∼1–2 dex higher (e.g., ne(C iii]λλ1907,9) ∼ 104 cm−3) than those inferred from their optical counterparts (e.g., ne([S ii]λλ6717,31) ∼ 102 cm−3; ne([Ar iv]λλ4714,41) ∼ 103 cm−3). Te derived from the hybrid ratio [O iii] λ1666/λ5007 proves to be reliable, implying differences in determining 12+log(O/H) compared to the optical counterpart O iii] λ4363/[O iii] λ5007 within ∼ ±0.3 dex. We also investigate the relation between the stellar and gas E(B − V), finding consistent values at high specific star formation rates (sSFRs; log(sSFR) ≳ -8 yr−1), while at low sSFRs we confirmed an excess of dust attenuation in the gas. Finally, we investigate UV line ratios and equivalent widths to provide correlations with 12+log(O/H) and log(U), but note that there are degeneracies between the two. With this suite of UV-based diagnostics, we illustrate the pivotal role CLASSY plays in understanding the chemical and physical properties of high-z systems that JWST can observe in the rest-frame UV.
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| 17. |
- Naidu, Rohan P., et al.
(author)
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The synchrony of production and escape : half the bright Lyα emitters at z ≈ 2 have Lyman continuum escape fractions ≈50 per cent
- 2022
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 510:3, s. 4582-4607
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Journal article (peer-reviewed)abstract
- The ionizing photon escape fraction [Lyman continuum (LyC) fesc] of star-forming galaxies is the single greatest unknown in the reionization budget. Stochastic sightline effects prohibit the direct separation of LyC leakers from non-leakers at significant redshifts. Here we circumvent this uncertainty by inferring fesc using resolved (R > 4000) Lyman α (Lyα) profiles from the X-SHOOTER Lyα survey at z = 2 (XLS-z2). With empirically motivated criteria, we use Lyα profiles to select leakers (fesc>20 per centfesc>20 per cent) and non-leakers (fesc<5 per centfesc<5 per cent) from a representative sample of >0.2L* Lyman α emitters (LAEs). We use median stacked spectra of these subsets over λrest ≈ 1000–8000 Å to investigate the conditions for LyC fesc. Our stacks show similar mass, metallicity, MUV, and βUV. We find the following differences between leakers versus non-leakers: (i) strong nebular C IV and He II emission versus non-detections; (ii) [O III]/[O II] ≈ 8.5 versus ≈3; (iii) Hα/Hβ indicating no dust versus E(B − V) ≈ 0.3; (iv) Mg II emission close to the systemic velocity versus redshifted, optically thick Mg II; and (v) Lyα fesc of ≈50 per cent≈50 per cent versus ≈10 per cent≈10 per cent. The extreme equivalent widths (EWs) in leakers ([O III]+Hβ≈1100Hβ≈1100 Å rest frame) constrain the characteristic time-scale of LyC escape to ≈3–10 Myr bursts when short-lived stars with the hardest ionizing spectra shine. The defining traits of leakers – extremely ionizing stellar populations, low column densities, a dust-free, high-ionization state interstellar medium (ISM) – occur simultaneously in the fesc>20 per centfesc>20 per cent stack, suggesting they are causally connected, and motivating why indicators like [O III]/[O II] may suffice to constrain fesc at z > 6 with the James Webb Space Telescope (JWST). The leakers comprise half of our sample, have a median LyCfesc≈50 per centfesc≈50 per cent (conservative range: 20−55 per cent20−55 per cent), and an ionizing production efficiency log(ξion/Hz erg−1)≈25.9log(ξion/Hz erg−1)≈25.9 (conservative range: 25.7–25.9). These results show LAEs – the type of galaxies rare at z ≈ 2, but that become the norm at higher redshift – are highly efficient ionizers, with extreme ξion and prolific fesc occurring in sync.
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| 18. |
- Sipeky, C, et al.
(author)
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4th ESPT Conference: pharmacogenomics and personalized medicine - research progress and clinical implementation
- 2019
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In: Pharmacogenomics. - : Future Medicine Ltd. - 1744-8042 .- 1462-2416. ; 20:15, s. 1063-1069
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Journal article (peer-reviewed)abstract
- The Fourth European Society of Pharmacogenomics and Personalized Therapy biennial conference was organized in collaboration with the Italian Society of Personalized Medicine (SIMeP) and was held at Benedictine Monastery of San Nicolò l’Arena in Catania, Sicily (Italy) on 4–7 October 2017. The congress addressed the research progress and clinical implementation in pharmacogenomics and personalized medicine. The Fourth European Society of Pharmacogenomics and Personalized Therapy congress brought together leading international scientists and healthcare professionals actively working in the fields of pharmacogenomics and personalized therapy. Altogether, 25 speakers in 15 session comprehensively covered broad spectrum of pharmacogenetics and pharmacogenomics research, clinical applications in different clinical disciplines attended by 270 delegates.
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