Throughout the Ebola virus disease (EVD) epidemic in West Africa, field laboratory testing for EVD has relied on complex, multi-step real-time reverse transcription PCR (RT-PCR) assays; an accurate ...sample-to-answer RT-PCR test would reduce time to results and potentially increase access to testing. We evaluated the performance of the Cepheid GeneXpert Ebola assay on clinical venipuncture whole blood (WB) and buccal swab (BS) specimens submitted to a field biocontainment laboratory in Sierra Leone for routine EVD testing by RT-PCR ("Trombley assay").
This study was conducted in the Public Health England EVD diagnostic laboratory in Port Loko, Sierra Leone, using residual diagnostic specimens remaining after clinical testing. EDTA-WB specimens (n = 218) were collected from suspected or confirmed EVD patients between April 1 and July 20, 2015. BS specimens (n = 71) were collected as part of a national postmortem screening program between March 7 and July 20, 2015. EDTA-WB and BS specimens were tested with Xpert (targets: glycoprotein GP and nucleoprotein NP genes) and Trombley (target: NP gene) assays in parallel. All WB specimens were fresh; 84/218 were tested in duplicate on Xpert to compare WB sampling methods (pipette versus swab); 43/71 BS specimens had been previously frozen. In all, 7/218 (3.2%) WB and 7/71 (9.9%) BS samples had Xpert results that were reported as "invalid" or "error" and were excluded, leaving 211 WB and 64 BS samples with valid Trombley and Xpert results. For WB, 22/22 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 84.6%-100%), and 181/189 Trombley-negative samples were Xpert-negative (specificity 95.8%, 95% confidence interval (CI) 91.8%-98.2%). Seven of the eight Trombley-negative, Xpert-positive (Xpert cycle threshold Ct range 37.7-43.4) WB samples were confirmed to be follow-up submissions from previously Trombley-positive EVD patients, suggesting a revised Xpert specificity of 99.5% (95% CI 97.0%-100%). For Xpert-positive WB samples (n = 22), Xpert NP Ct values were consistently lower than GP Ct values (mean difference -4.06, 95% limits of agreement -6.09, -2.03); Trombley (NP) Ct values closely matched Xpert NP Ct values (mean difference -0.04, 95% limits of agreement -2.93, 2.84). Xpert results (positive/negative) for WB sampled by pipette versus swab were concordant for 78/79 (98.7%) WB samples, with comparable Ct values for positive results. For BS specimens, 20/20 Trombley-positive samples were Xpert-positive (sensitivity 100%, 95% CI 83.2%-100%), and 44/44 Trombley-negative samples were Xpert-negative (specificity 100%, 95% CI 92.0%-100%). This study was limited to testing residual diagnostic samples, some of which had been frozen before use; it was not possible to test the performance of the Xpert Ebola assay at point of care.
The Xpert Ebola assay had excellent performance compared to an established RT-PCR benchmark on WB and BS samples in a field laboratory setting. Future studies should evaluate feasibility and performance outside of a biocontainment laboratory setting to facilitate expanded access to testing.
Reports of ChAdOx1 vaccine-associated thrombocytopenia and vascular adverse events have led to some countries restricting its use. Using a national prospective cohort, we estimated associations ...between exposure to first-dose ChAdOx1 or BNT162b2 vaccination and hematological and vascular adverse events using a nested incident-matched case-control study and a confirmatory self-controlled case series (SCCS) analysis. An association was found between ChAdOx1 vaccination and idiopathic thrombocytopenic purpura (ITP) (0-27 d after vaccination; adjusted rate ratio (aRR) = 5.77, 95% confidence interval (CI), 2.41-13.83), with an estimated incidence of 1.13 (0.62-1.63) cases per 100,000 doses. An SCCS analysis confirmed that this was unlikely due to bias (RR = 1.98 (1.29-3.02)). There was also an increased risk for arterial thromboembolic events (aRR = 1.22, 1.12-1.34) 0-27 d after vaccination, with an SCCS RR of 0.97 (0.93-1.02). For hemorrhagic events 0-27 d after vaccination, the aRR was 1.48 (1.12-1.96), with an SCCS RR of 0.95 (0.82-1.11). A first dose of ChAdOx1 was found to be associated with small increased risks of ITP, with suggestive evidence of an increased risk of arterial thromboembolic and hemorrhagic events. The attenuation of effect found in the SCCS analysis means that there is the potential for overestimation of the reported results, which might indicate the presence of some residual confounding or confounding by indication. Public health authorities should inform their jurisdictions of these relatively small increased risks associated with ChAdOx1. No positive associations were seen between BNT162b2 and thrombocytopenic, thromboembolic and hemorrhagic events.
The precise measurement of mechanical stress at the nanoscale is of fundamental and technological importance. In principle, all six independent variables of the stress tensor, which describe the ...direction and magnitude of compression/tension and shear stress in a solid, can be exploited to tune or enhance the properties of materials and devices. However, existing techniques to probe the local stress are generally incapable of measuring the entire stress tensor. Here, we make use of an ensemble of atomic-sized in situ strain sensors in diamond (nitrogen-vacancy defects) to achieve spatial mapping of the full stress tensor, with a submicrometer spatial resolution and a sensitivity of the order of 1 MPa (10 MPa) for the shear (axial) stress components. To illustrate the effectiveness and versatility of the technique, we apply it to a broad range of experimental situations, including mapping the stress induced by localized implantation damage, nanoindents, and scratches. In addition, we observe surprisingly large stress contributions from functional electronic devices fabricated on the diamond and also demonstrate sensitivity to deformations of materials in contact with the diamond. Our technique could enable in situ measurements of the mechanical response of diamond nanostructures under various stimuli, with potential applications in strain engineering for diamond-based quantum technologies and in nanomechanical sensing for on-chip mass spectroscopy.
Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were ...quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.
Summary
Background
Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but ...there is a paucity of data on genotype–phenotype correlation in some populations.
Objectives
We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype–phenotype correlation.
Methods
Deep phenotyping was undertaken by history‐taking and clinical examination. DNA was screened for mutations using a next‐generation sequencing ichthyosis gene panel and Sanger sequencing.
Results
Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self‐improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype.
Conclusions
These data refine genotype–phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management.
What's already known about this topic?
Recessive forms of ichthyosis are rare but often difficult to diagnose.
Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1.
Some phenotypic features may associate with certain gene mutations, but paradigms for genotype–phenotype correlation need refining.
What does this study add?
The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%).
New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision.
In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.
Linked Editorial: Steele and O’Toole. Br J Dermatol 2020; 182:521–522.
Plain language summary available online
We present a multi-wavelength analysis of 52 submillimeter galaxies (SMGs), identified using ALMA 870 m continuum imaging in a pilot program to precisely locate bright SCUBA-2-selected submillimeter ...sources in the UKIDSS Ultra Deep Survey (UDS) field. Using the available deep (especially near-infrared) panoramic imaging of the UDS field at optical-to-radio wavelengths we characterize key properties of the SMG population. The median photometric redshift of the bright ALMA/SCUBA-2 UDS (AS2UDS) SMGs that are detected in a sufficient number of wavebands to derive a robust photometric redshift is z = 2.65 0.13. However, similar to previous studies, 27% of the SMGs are too faint at optical-to-near-infrared wavelengths to derive a reliable photometric redshift. Assuming that these SMGs lie at z 3 raises the median redshift of the full sample to z = 2.9 0.2. A subset of 23 unlensed, bright AS2UDS SMGs have sizes measured from resolved imaging of their rest-frame far-infrared emission. We show that the extent and luminosity of the far-infrared emission are consistent with the dust emission arising from regions that are, on average, optically thick at a wavelength of (1 dispersion of 55-90 m). Using the dust masses derived from our optically thick spectral energy distribution models, we determine that these galaxies have a median hydrogen column density of NH = 9.8 × 1023 cm−2, or a corresponding median V-band obscuration of Av = 540 mag, averaged along the line of sight to the source of their rest-frame ∼200 m emission. We discuss the implications of this extreme attenuation by dust for the multi-wavelength study of dusty starbursts and reddening-sensitive tracers of star formation.
The Whole Atmosphere Community Climate Model version 6 (WACCM6) is a major update of the whole atmosphere modeling capability in the Community Earth System Model (CESM), featuring enhanced physical, ...chemical and aerosol parameterizations. This work describes WACCM6 and some of the important features of the model. WACCM6 can reproduce many modes of variability and trends in the middle atmosphere, including the quasi‐biennial oscillation, stratospheric sudden warmings, and the evolution of Southern Hemisphere springtime ozone depletion over the twentieth century. WACCM6 can also reproduce the climate and temperature trends of the 20th century throughout the atmospheric column. The representation of the climate has improved in WACCM6, relative to WACCM4. In addition, there are improvements in high‐latitude climate variability at the surface and sea ice extent in WACCM6 over the lower top version of the model (CAM6) that comes from the extended vertical domain and expanded aerosol chemistry in WACCM6, highlighting the importance of the stratosphere and tropospheric chemistry for high‐latitude climate variability.
Plain Language Summary
This manuscript describes the Whole Atmosphere Community Climate Model Version 6 (WACCM6), a chemistry and climate model which extends up to 140 km in the upper atmosphere. WACCM6 reproduces many important features of the climate system, and the addition of detailed chemistry and the higher than normal model top produces slightly improved simulations of the Arctic region.
Key Points
WACCM6 is a major upgrade to previous versions
WACCM6 can reproduce many modes of variability and trends in the middle atmosphere
WACCM6 provides improvements in high‐latitude climate variability at the surface and sea ice extent over a low top model
Conjunctivitis in dupilumab clinical trials Akinlade, B.; Guttman‐Yassky, E.; Bruin‐Weller, M. ...
British journal of dermatology (1951),
September 2019, Letnik:
181, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Summary
Background
Dupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis ...(AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo.
Objectives
To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials.
Methods
We evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47).
Results
In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis.
Conclusions
Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study.
What's already known about this topic?
Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD).
In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo.
Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare.
Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis.
What does this study add?
This analysis confirms and extends the results of the individual clinical trials.
Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation‐regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis.
Patients who responded well to dupilumab had reduced incidence of conjunctivitis.
Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab‐treated patients with AD.
Linked Editorial: Chia‐Yu Chu. Br J Dermatol 2019; 181:436–437.
Plain language summary available online
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This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals ...in the era of combination antiretroviral therapy (CART).
A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment).
Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups).
The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
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