ObjectivesThe epidemiological evidence for adverse health effects of long-term exposure to air and noise pollution from traffic is not coherent. Further, the relative roles of background versus near ...traffic pollution concentrations in this process are unclear. We investigated relationships between modelled concentrations of air and noise pollution from traffic and incident cardiorespiratory disease in London.MethodsAmong 211 016 adults aged 40–79 years registered in 75 Greater London practices between 2005 and 2011, the first diagnosis for a range of cardiovascular and respiratory outcomes were identified from primary care and hospital records. Annual baseline concentrations for nitrogen oxide (NOx), particulate matter with a median aerodynamic diameter <2.5 μm (PM2.5) attributable to exhaust and non-exhaust sources, traffic intensity and noise were estimated at 20 m2 resolution from dispersion models, linked to clinical data via residential postcode. HRs were adjusted for confounders including smoking and area deprivation.ResultsThe largest observed associations were between traffic-related air pollution and heart failure (HR=1.10 for 20 μg/m3 change in NOx, 95% CI 1.01 to 1.21). However, no other outcomes were consistently associated with any of the pollution indicators, including noise. The greater variations in modelled air pollution from traffic between practices, versus within, hampered meaningful fine spatial scale analyses.ConclusionsThe associations observed with heart failure may suggest exacerbatory effects rather than underlying chronic disease. However, the overall failure to observe wider associations with traffic pollution may reflect that exposure estimates based on residence inadequately represent the relevant pattern of personal exposure, and future studies must address this issue.
Glioma intratumoral heterogeneity enables adaptation to challenging microenvironments and contributes to therapeutic resistance. We integrated 914 single-cell DNA methylomes, 55,284 single-cell ...transcriptomes and bulk multi-omic profiles across 11 adult IDH mutant or IDH wild-type gliomas to delineate sources of intratumoral heterogeneity. We showed that local DNA methylation disorder is associated with cell-cell DNA methylation differences, is elevated in more aggressive tumors, links with transcriptional disruption and is altered during the environmental stress response. Glioma cells under in vitro hypoxic and irradiation stress increased local DNA methylation disorder and shifted cell states. We identified a positive association between genetic and epigenetic instability that was supported in bulk longitudinally collected DNA methylation data. Increased DNA methylation disorder associated with accelerated disease progression and recurrently selected DNA methylation changes were enriched for environmental stress response pathways. Our work identified an epigenetically facilitated adaptive stress response process and highlights the importance of epigenetic heterogeneity in shaping therapeutic outcomes.
BackgroundHigh ambient summer temperatures have been shown to influence daily mortality in cities across Europe. Quantification of the population mortality burden attributable to heat is crucial to ...the development of adaptive approaches. The impact of summer heat on mortality for 15 European cities during the 1990s was evaluated, under hypothetical temperature scenarios warmer and cooler than the mean and under future scenarios derived from the Intergovernmental Panel on Climate Change Special Report on Emission Scenarios (SRES).MethodsA Monte Carlo approach was used to estimate the number of deaths attributable to heat for each city. These estimates rely on the results of a Bayesian random-effects meta-analysis that combines city-specific heat-mortality functions.ResultsThe number of heat-attributable deaths per summer ranged from 0 in Dublin to 423 in Paris. The mean attributable fraction of deaths was around 2%. The highest impact was in three Mediterranean cities (Barcelona, Rome and Valencia) and in two continental cities (Paris and Budapest). The largest impact was on persons over 75 years; however, in some cities, important proportions of heat-attributable deaths were also found for younger adults. Heat-attributable deaths markedly increased under warming scenarios. The impact under SRES scenarios was slightly lower or comparable to the impact during the observed hottest year.ConclusionsCurrent high summer ambient temperatures have an important impact on European population health. This impact is expected to increase in the future, according to the projected increase of mean ambient temperatures and frequency, intensity and duration of heat waves.
Hypoplastic left heart syndrome (HLHS) covers a spectrum of rare congenital anomalies characterised by a non-apex forming left ventricle and stenosis/atresia of the mitral and aortic valves. Despite ...many studies, the causes of HLHS remain unclear and there are conflicting views regarding the role of flow, valvar or myocardial abnormalities in its pathogenesis, all of which were proposed prior to the description of the second heart field. Our aim was to re-evaluate the patterns of malformation in HLHS in relation to recognised cardiac progenitor populations, with a view to providing aetiologically useful sub-groupings for genomic studies.
We examined 78 hearts previously classified as HLHS, with subtypes based on valve patency, and re-categorised them based on their objective ventricular phenotype. Three distinct subgroups could be identified: slit-like left ventricle (24%); miniaturised left ventricle (6%); and thickened left ventricle with endocardial fibroelastosis (EFE; 70%). Slit-like ventricles were always found in combination with aortic atresia and mitral atresia. Miniaturised left ventricles all had normally formed, though smaller aortic and mitral valves. The remaining group were found to have a range of aortic valve malformations associated with thickened left ventricular walls despite being described as either atresia or stenosis. The degree of myocardial thickening was not correlated to the degree of valvar stenosis. Lineage tracing in mice to investigate the progenitor populations that form the parts of the heart disrupted by HLHS showed that whereas Nkx2-5-Cre labelled myocardial and endothelial cells within the left and right ventricles, Mef2c-AHF-Cre, which labels second heart field-derived cells only, was largely restricted to the endocardium and myocardium of the right ventricle. However, like Nkx2-5-Cre, Mef2c-AHF-Cre lineage cells made a significant contribution to the aortic and mitral valves. In contrast, Wnt1-Cre made a major contribution only to the aortic valve. This suggests that discrete cardiac progenitors might be responsible for the patterns of defects observed in the distinct ventricular sub-groups.
Only the slit-like ventricle grouping was found to map to the current nomenclature: the combination of mitral atresia with aortic atresia. It appears that slit-like and miniature ventricles also form discrete sub-groups. Thus, reclassification of HLHS into subgroups based on ventricular phenotype, might be useful in genetic and developmental studies in investigating the aetiology of this severe malformation syndrome.
Sesamol is a phenolic derivative. Its antioxidant activity is low than that of Trolox and depends on benzodioxole moiety. Thus, a molecular modification strategy through alkylation, inspired by ...natural and synthetic antioxidants, was studied by molecular modeling at the DFT/B3LYP level of theory by comparing the 6-31+G(d,p) and 6-311++G(2d,2p) basis sets. All proposed derivatives were compared to classical related antioxidants such as Trolox,
-butylated hydroxytoluene (BHT) and
-butylated hydroxyanisole (BHA). According to our results, molecular orbitals, single electron or hydrogen-atom transfers, spin density distributions, and alkyl substitutions at the ortho positions related to phenol moiety were found to be more effective than any other positions. The trimethylated derivative was more potent than Trolox.
-Butylated derivatives were stronger than all other alkylated derivatives and may be new alternative forms of modified antioxidants from natural products with applications in the chemical, pharmaceutical, and food industries.
Context.
The sub-Jovian, or Neptunian, desert is a previously identified region of parameter space where there is a relative dearth of intermediate-mass planets with short orbital periods.
Aims.
We ...present the discovery of a new transiting planetary system within the Neptunian desert, NGTS-14.
Methods.
Transits of NGTS-14Ab were discovered in photometry from the Next Generation Transit Survey (NGTS). Follow-up transit photometry was conducted from several ground-based facilities, as well as extracted from TESS full-frame images. We combine radial velocities from the HARPS spectrograph with the photometry in a global analysis to determine the system parameters.
Results.
NGTS-14Ab has a radius that is about 30 per cent larger than that of Neptune (0.444 ± 0.030
R
Jup
) and is around 70 per cent more massive than Neptune (0.092 ± 0.012
M
Jup
). It transits the main-sequence K1 star, NGTS-14A, with a period of 3.54 days, just far away enough to have maintained at least some of its primordial atmosphere. We have also identified a possible long-period stellar mass companion to the system, NGTS-14B, and we investigate the binarity of exoplanet host stars inside and outside the Neptunian desert using
Gaia
.
Background
An objective of the phase 3 HELP Study was to investigate the effect of lanadelumab on health‐related quality of life (HRQoL) in patients with hereditary angioedema (HAE).
Methods
Patients ...with HAE‐1/2 received either lanadelumab 150 mg every 4 weeks (q4wks; n = 28), 300 mg q4wks (n = 29), 300 mg every 2 weeks (q2wks; n = 27), or placebo (n = 41) for 26 weeks (days 0–182). The Angioedema Quality of Life Questionnaire (AE‐QoL) was administered monthly, consisting of four domain (functioning, fatigue/mood, fears/shame, nutrition) and total scores. The generic EQ‐5D‐5L questionnaire was administered on days 0, 98, and 182. Comparisons were made between placebo and (a) all lanadelumab‐treated patients and (b) individual lanadelumab groups for changes in scores (day 0–182) and proportions achieving the minimal clinically important difference (MCID, −6) in AE‐QoL total score.
Results
Compared with the placebo group, the lanadelumab total group demonstrated significantly greater improvements in AE‐QoL total and domain scores (mean change, −13.0 to −29.3; p < 0.05 for all); the largest improvement was in functioning. A significantly greater proportion of the lanadelumab total group achieved the MCID (70% vs 37%; p = 0.001). The lanadelumab 300 mg q2wks group had the highest proportion (81%; p = 0.001) and was 7.2 times more likely to achieve the MCID than the placebo group. Mean EQ‐5D‐5L scores at day 0 were high in all groups, indicating low impairment, with no significant changes at day 182.
Conclusion
Patients with HAE‐1/2 experienced significant and clinically meaningful improvements in HRQoL measured by AE‐QoL following lanadelumab treatment in the HELP Study.
In the phase 3 HELP Study, HRQoL (health‐related quality of life) of patients with HAE (hereditary angioedema)‐1/2 was evaluated using the angioedema‐specific AE‐QoL (Angioedema Quality of Life Questionnaire). After 26 weeks, lanadelumab‐treated patients experienced significantly greater HRQoL improvements than placebo‐treated patients. Patients receiving lanadelumab 300 mg q2wks (every 2 weeks) were most likely to see clinically meaningful benefit, with 81% reaching the MCID (minimal clinically important difference) and seven times greater odds vs placebo for this achievement.
Abbreviations: AE‐QoL, Angioedema Quality of Life Questionnaire; HAE, hereditary angioedema; HRQoL, health‐related quality of life; MCID, minimal clinically important difference; q2wks, every 2 weeks; q4wks, every 4 weeks.
Background Suboptimal antiretroviral (ART) adherence can lead to virologic failure with consequent HIV-1 resistance. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a powerful biomarker ...of cumulative adherence, predictive of future viremia. It has been associated with resistance in Persons With HIV (PWH) in South Africa and the US. We explored the relationship of TFV-DP concentrations with antiretroviral drug resistance at the time of treatment failure in SA. Methods Adult PWH from health clinics in Cape Town, South Africa on efavirenz-based first-line ART containing tenofovir disoproxil fumarate (TDF) with an undetectable (< 50 copies/mL) HIV-1 viral load (VL) were prospectively enrolled in an observational cohort for 12 months. Monthly study visits included blood collection for HIV-1 VL and DBS for TFV-DP. The first confirmed viral breakthrough (VB) > 400 copies/mL triggered HIV-1 genotyping at the subsequent visit. An electronic adherence (EA) device monitored ART adherence in real-time, estimated as a percent for the 30-days prior to VB. Wilcoxon rank sum test was used to compare median IQR TFV-DP by genotype outcome. Results Of 250 individuals, (n = 195, 78% women), 21 experienced VB, with a median of 5 4;7 months on study, and a median EA of 33.3 13.3;53.3%. Demographic characteristics between those with and without VB were similar. Median VL at VB was 4.0 3.2;4.5 log copies/mL. TFV-DP concentrations trended down towards the VB visit. Median TFV-DP concentrations were significantly higher in those HIV-1 genotype did not amplify due to being virally suppressed at the subsequent visit (n = 10; 380 227-661 fmol/punch, p = 0.035; EA 45 24.9; 59.2%); than in those who were successfully genotyped with evidence of drug resistance (n = 5, 241 150-247 fmol/punch, EA 20 6.7;36.7%) and in individuals who did not have resistance (n = 3, 39.9 16.6; 93.9 fmol/punch; EA 33.3 16-38%). Three genotype collections were not done. Only non-nucleoside reverse transcriptase inhibitor-associated mutations were identified on resistance testing. (K103N, E138K, Y118H). Conclusion TFV-DP in DBS showed a step-wise inverse relationship with VB and drug resistance, with evidence of low cumulative ART adherence in PWH who developed antiretroviral resistance. Monitoring TFV-DP concentrations could be a valuable tool for predicting future VB and future resistance. Keywords: South Africa, HIV resistance, Adherence, Dried blood spots, Tenofovir diphosphate
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