Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

BACKGROUND: The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. METHODS: HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months. RESULTS: HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10−12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. CONCLUSIONS: Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile

Brown Carbon Aerosol in Urban Xi’an, Northwest China: TheComposition and Light Absorption Properties

Light-absorbing organic carbon (i.e., brown carbon or BrC) in the atmospheric aerosol has significant contribution to light absorption and radiative forcing. However, the link between BrC optical properties and chemical composition remains poorly constrained. In this study, we combine spectrophotometric measurements and chemical analyses of BrC samples collected from July 2008 to June 2009 in urban Xi'an, Northwest China. Elevated BrC was observed in winter (5 times higher than in summer), largely due to increased emissions from wintertime domestic biomass burning. The light absorption coefficient of methanol-soluble BrC at 365 nm (on average approximately twice that of water-soluble BrC) was found to correlate strongly with both parent polycyclic aromatic hydrocarbons (parent-PAHs, 27 species) and their carbonyl oxygenated derivatives (carbonyl-OPAHs, 15 species) in all seasons (r(2) > 0.61). These measured parent-PAHs and carbonyl-OPAHs account for on average similar to 1.7% of the overall absorption of methanol-soluble BrC, about 5 times higher than their mass fraction in total organic carbon (OC, similar to 0.35%). The fractional solar absorption by BrC relative to element carbon (EC) in the ultraviolet range (300-400 nm) is significant during winter (42 +/- 18% for water-soluble BrC and 76 +/- 29% for methanol-soluble BrC), which may greatly affect the radiative balance and tropospheric photochemistry and therefore the climate and air quality

Finite Mixtures of Nonlinear Mixed-Effects Models for Longitudinal Data

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biostatistics & Computational Biology, 2017.Finite mixture models are increasingly used to model distributions in multivariate regression settings where outcomes and covariates exhibit heterogeneous relationships. When observations are collected repeatedly within subjects, for example longitudinally, these models must be adapted to account for potential dependencies. In this thesis, we consider a class of finite mixture regression models that is suitable for longitudinal data structures. The proposed model captures inter-subject variability and intra-subject dependencies with random effects and allows both mixing proportions and component densities to depend on covariates. We propose a new version of the stochastic approximation expectation maximization (SAEM) algorithm, which we call the Newton-Raphson SAEM (NR-SAEM) algorithm for maximum likelihood (ML) estimation. The implementation of our proposed algorithm requires sampling unobservable random effects from their posterior distributions using Markov Chain Monte Carlo (MCMC) methods, and reduces stochastic variability by estimating latent group indicators unconditional on random effects. The proposed method is demonstrated using both simulated data and real data of repeated hormone levels over a key period of the menstrual cycle. We compare the NR-SAEM algorithm to the standard expectation maximization (EM) and the mixture SAEM (MSAEM) algorithms. We find that the NR-SAEM algorithm performed comparably to the standard EM algorithm that converged to the ML estimators for finite mixture regression models with linear random effects, and it exhibited better convergence than the MSAEM algorithm in simulations. Application of our proposed model to the hormone level data suggests that women’s hormone trajectories over a key part of the menstrual cycle may follow more than one type of pattern, suggesting several subpopulations which differ with respect to the distributions of BMI and PFOS exposure

Changes in Source-Specific Black Carbon Aerosol and the Induced Radiative Effects Due to the COVID-19 Lockdown

The impacts of anthropogenic emissions on the reduction of source-specific equivalent black carbon (eBC) aerosols and their direct radiative effects (DREs) were investigated during the lockdown of the coronavirus outbreak in a megacity of China in 2020. Five eBC sources were identified using a hybrid environmental receptor model. Results showed that biomass burning, traffic-related emissions, and coal combustion were the dominant contributors to eBC. The generalized additive model indicated that the reduction of traffic-related eBC during the lockdown was entirely attributed to the decrease of emissions. Decreased biomass-burning activities and favorable meteorological factors are both important drivers for the biomass-burning eBC reduction during the lockdown. A radiative transfer model showed that the DRE efficiency of eBC from biomass burning was the strongest, followed by coal combustion and traffic-related emissions. This study highlights that aggressive reduction in the consumption of residential solid fuels would be effective in achieving climate change mitigation

Concentration and sources of atmospheric nitrous acid (HONO) at an urban site in Western China

Highly time-resolved measurements of nitrous acid (HONO) were carried out with a highly sensitive long path absorption photometer (LOPAP) at an urban site of Xi'an in Western China from 24 July to 6 August 2015 to investigate the atmospheric variations, sources, and formation pathways of HONO. The concentrations of HONO vary from 0.02 to 43 ppbv with an average of 1.12 ppbv for the entire measurement period. The variation trends of HONO and NO2 are very similar and positively correlated which, together with the similar diurnal profiles of HONO/NO2 ratio and HONO, suggest the importance of heterogeneous conversion of HONO from NO2. The nocturnal HONO level is governed by heterogeneous formation from NO2, followed by homogeneous formation of NO with OH and then by direct emissions. Further, it is found that the heterogeneous formation of HONO is largely affected by relative humidity and aerosol surface. Daytime HONO budget analysis indicates that an additional unknown source with HONO production rate of 0.75 ppbv h(-1) is required to explain the observed HONO concen-HONO source and formation tration, which contributes 60.8% of the observed daytime HONO. (C) 2017 Elsevier B.V. All rights reserved

Water-Insoluble Organics Dominate Brown Carbon in Wintertime Urban Aerosol of China: Chemical Characteristics and Optical Properties

The chromophores responsible for light absorption in atmospheric brown carbon (BrC) are not well characterized, which hinders our understanding of BrC chemistry, the links with optical properties, and accurate model representations of BrC to global climate and atmospheric oxidative capacity. In this study, the light absorption properties and chromophore composition of three BrC fractions of different polarities were characterized for urban aerosol collected in Xi'an and Beijing in winter 2013-2014. These three BrC fractions show large differences in light absorption and chromophore composition, but the chromophores responsible for light absorption are similar in Xi'an and Beijing. Water-insoluble BrC (WI-BrC) fraction dominates the total BrC absorption at 365 nm in both Xi'an (51 +/- 5%) and Beijing (62 +/- 13%), followed by a humic-like fraction (HULIS-BrC) and high-polarity water-soluble BrC. The major chromophores identified in HULIS-BrC are nitrophenols and carbonyl oxygenated polycyclic aromatic hydrocarbons (OPAHs) with 2-3 aromatic rings (in total 18 species), accounting for 10% and 14% of the light absorption of HULIS-BrC at 365 nm in Xi'an and Beijing, respectively. In comparison, the major chromophores identified in WI-BrC are PAHs and OPAHs with 4-6 aromatic rings (in total 16 species), contributing 6% and 8% of the light absorption of WI-BrC at 365 nm in Xi'an and Beijing, respectively

Impacts of short-term mitigation measures on PM2.5 and radiative effects: a case study at a regional background site near Beijing, China

Measurements at a background site near Beijing showed that pollution controls implemented during the 19th National Congress of the Communist Party of China (NC-CPC) were effective in reducing PM2.5. Mass concentrations of PM2.5 and its major chemical components were 20.6%-43.1% lower during the NCCPC-control period compared with a non-control period, and differences were greater on days with stable meteorological conditions. A receptor model showed that PM2.5 from traffic-related emissions, biomass burning, industrial processes, and mineral dust was 38.5%-77.8% lower during the NCCPC-control versus non-control period, but differences in PM2.5 from coal burning were small, and secondary sources were higher during the NCCPC-control period. During one pollution episode in the non-control period, secondary sources dominated, and the WRF-Chem model showed that the Beijing-Tianjin-Hebei (BTH) region contributed 73.6% of PM2.5 mass. A second pollution episode was linked to biomass burning, and BTH contributed 46.9% of PM2.5 mass. Calculations based on Interagency Monitoring of Protected Visual Environments (IMPROVE) algorithms showed that organic matter was the largest contributor to light extinction during the non-control period whereas NH4NO3 was the main contributor during the NCCPC. The Tropospheric Ultraviolet and Visible radiation model showed that the average direct radiative forcing (DRF) values at the Earth's surface were -14.0 and -19.3 W m(-2) during the NCCPC-control and non-control periods, respectively, and the DRF for the individual PM2.5 components were 22.7%-46.7% lower during the NCCPC. The information and dataset from this study will be useful for developing air pollution control strategies in the BTH region and for understanding associated aerosol radiative effects

Wintertime Optical Properties of Primary and Secondary Brown Carbon at a Regional Site in the North China Plain

The light-absorbing properties of atmospheric brown carbon (BrC) are poorly understood due to its complex chemical composition. Here, a black-carbon-tracer method was coupled with source apportionments of organic aerosol (OA) to explore the light-absorbing properties of primary and secondary BrC from the North China Plain (NCP). Primary emissions of BrC contributed more to OA light absorption than secondary processes, and biomass burning OA accounted for 60% of primary BrC absorption at lambda = 370 nm, followed by coal combustion OA (35%) and hydrocarbon-like OA (5%). Secondary BrC absorption was high in the early morning and later decreased due to the bleaching of chromophores. Nighttime aqueous-phase chemistry promoted the formation of secondary light-absorbing compounds and the production of strongly absorbing particles. Source analysis showed that the NCP region was the most important source for primary and secondary BrC subtypes at the study site. The mean direct radiative forcing for BrC was 0.15 W m(-2) (0.11 W m(-2) and 0.04 W m(-2) for the primary and secondary fractions, respectively). This study provides new information on the optical properties of primary and secondary BrC and highlights the importance of atmospheric oxidation on BrC absorption

Multi-Wavelength Light Absorption of Black and Brown Carbon at a High-Altitude Site on the Southeastern Margin of the Tibetan Plateau, China

The Tibetan Plateau (TP) is one of the world\u27s most sensitive areas for climate change, but the lack of information on light-absorption by aerosols limits the understanding of climate forcing feedbacks. Here, the contributions of black carbon (BC) and brown carbon (BrC) to light absorption and radiative forcing were investigated. Absorption Ångström exponents (α), mass absorption cross sections (MAC), and absorption coefficients (babs) for selected wavelengths were measured for a year of aerosol samples collected at Lulang on the southeast TP. Aerosol absorption at all wavelengths was strongest in the pre-monsoon when levoglucosan, a biomass burning indicator, was elevated. The contributions of BC, BrC, and dust to babs were decoupled. Results showed that dust contributed 8.5% to the total light absorption at 405 nm and 3.9% 808 nm. A two-component model indicated that BC and BrC contributed 48.7% and 44.0% to total babs at 405 nm but BrC had a smaller effect at middle-visible wavelengths. Elevated babs,non-dust,BC and babs,non-dust,BrC and a high αBrC but low αaerosol values in the pre-monsoon were attributed to biomass burning, which produces not only BrC but also BC which has a much lower α value. Average non-dust MACs for BC and BrC at 405 nm were 6.1 ± 2.8 and 0.72 ± 0.55 m2 g−1, respectively. Nonparametric statistical tests showed that the MACnon-dust,BC was relatively constant but MACnon-dust, BrC was more variable. In addition, BrC was correlated with non-dust babs,BC and MACnon-dust,BC in winter and the pre-monsoon, implying BrC and BC shared sources in those two seasons, but lower correlations in the monsoon and post-monsoon suggest that a mixture of sources impacted BrC (e.g., biogenic emission, secondary formation, etc.). Finally, the relative contributions of BrC to BC for radiative forcing from 405 to 808 nm were 29.4 ± 9.5% with no remarkable seasonal differences, confirming the importance of BrC to light absorption in the near UV throughout the year. As a result, the BrC absorption is an important additional factor which needs to be considered in atmospheric models, although the atmospheric heating by BC seems to be a larger climate forcer in this region