This book presents modern developments in time series econometrics that are applied to macroeconomic and financial time series. It attempts to bridge the gap between methods and realistic ...applications. This book contains the most important approaches to analyse time series which may be stationary or nonstationary. Modelling and forecasting univariate time series is the starting point. For multiple stationary time series Granger causality tests and vector autoregressive models are presented. For real applied work the modelling of nonstationary uni- or multivariate time series is most important. Therefore, unit root and cointegration analysis as well as vector error correction models play a central part. Modelling volatilities of financial time series with autoregressive conditional heteroskedastic models is also treated.
Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with aging that is characterized by the histopathological pattern of usual interstitial pneumonia. Although an ...understanding of the pathogenesis of IPF is incomplete, recent advances delineating specific clinical and pathologic features of IPF have led to better definition of the molecular pathways that are pathologically activated in the disease. In this review we highlight several of these advances, with a focus on genetic predisposition to IPF and how genetic changes, which occur primarily in epithelial cells, lead to activation of profibrotic pathways in epithelial cells. We then discuss the pathologic changes within IPF fibroblasts and the extracellular matrix, and we conclude with a summary of how these profibrotic pathways may be interrelated.
Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in ...supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1
SiglecF
transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.
Fibrotic interstitial lung disease (ILD) represents a large group of pulmonary disorders that are often progressive and associated with high morbidity and early mortality. Important advancements in ...the past 10 years have enabled a better understanding, characterisation, and treatment of these diseases. This Series paper summarises the current approach to treatment of fibrotic ILDs, both pharmacological and non-pharmacological, including recent discoveries and practice-changing clinical trials. We further outline controversies and challenges, with discussion of evolving concepts and future research directions.
We report the generation of entanglement between two individual 87Rb atoms in hyperfine ground states |F=1,M=1> and |F=2,M=2> which are held in two optical tweezers separated by 4 microm. Our scheme ...relies on the Rydberg blockade effect which prevents the simultaneous excitation of the two atoms to a Rydberg state. The entangled state is generated in about 200 ns using pulsed two-photon excitation. We quantify the entanglement by applying global Raman rotations on both atoms. We measure that 61% of the initial pairs of atoms are still present at the end of the entangling sequence. These pairs are in the target entangled state with a fidelity of 0.75.
Alzheimer's disease is one of the most heritable diseases in elderly people and the most common type of dementia. In addition to the major genetic determinant of Alzheimer's disease, the APOE gene, ...23 genetic variants have been associated with the disease. We assessed the effects of these variants and APOE on cumulative risk and age at onset of Alzheimer's disease and all-cause dementia.
We studied incident dementia in cognitively healthy participants (aged >45 years) from the community-based Rotterdam Study, an ongoing prospective cohort study based in Rotterdam, the Netherlands, focusing on neurological, cardiovascular, endocrine, and ophthalmological disorders, and other diseases in elderly people. The Rotterdam Study comprises participants in three baseline cohorts (initiated in 1990, 2000, and 2006), who are re-invited to the research centre every 3–4 years, and continuously monitored by records from general practitioners and medical specialists. Cumulative incidence curves up to age 100 years were calculated for Alzheimer's disease and dementia, taking into account mortality as a competing event. These risk curves were stratified by APOE genotypes, tertiles of a weighted genetic risk score (GRS) of 23 Alzheimer's disease-associated genetic variants, and parental history of dementia.
12 255 of 14 926 participants (58·5% women) from the Rotterdam Study were included in this study. During a median follow-up of 11·0 years (IQR 4·9–15·9; 133 123 person years), 1609 participants developed dementia, of whom 1262 (78%) were classified as having Alzheimer's disease; 3310 people died of causes other than dementia. Both APOE and the GRS significantly modified the risks of Alzheimer's disease and dementia. There was evidence for a significant interaction between APOE genotypes and the GRS for the association with Alzheimer's disease (p=0·03) and dementia (p=0·04); the risk for carriers homozygous for APOE ε4 was modified most by the GRS. In carriers homozygous for APOE ε4, the difference between the high-risk tertile and the low-risk tertile by age 85 years was 27·0% for Alzheimer's disease (p=8·5 × 10−3) and 37·2% for dementia (p=2·2 × 10−4), which translates to a 7–10 year difference in age at onset. Comparing the risk extremes, which were carriers homozygous for APOE ε2 or heterozygous with one copy each of the ε2 and ε3 alleles in the low-risk tertile of the GRS versus carriers homozygous for APOE ε4 in the high-risk tertile of the GRS, the difference in risk by age 85 years was 58·6% (4·1% vs 62·7%; p=6·2 × 10−13) for Alzheimer's disease, and 70·3% (7·2% vs 77·5%; p=3·0 × 10−23) for dementia. These risk differences translate into an 18–29 years difference in age at onset for Alzheimer's disease and an 18–23 year difference in age at onset dementia. This difference becomes more pronounced when parental history of dementia is considered (difference in risk 83·8%; p=1·1 × 10−20).
Common variants with small individual effects jointly modify the risk and age at onset of Alzheimer's disease and dementia, particularly in APOE ε4 carriers. These findings highlight the potential of common variants in determining Alzheimer's disease risk.
None.
With the onset of prevention trials for individuals at high risk for Alzheimer disease, there is increasing need for accurate risk prediction to inform study design and enrollment, but available risk ...estimates are limited. We developed risk estimates for the incidence of mild cognitive impairment (MCI) or dementia among cognitively unimpaired individuals by APOE-e4 dose for the genetic disclosure process of the Alzheimer's Prevention Initiative Generation Study, a prevention trial in cognitively unimpaired APOE-e4/e4 homozygote individuals.
We included cognitively unimpaired individuals aged 60-75 y, consistent with Generation Study eligibility criteria, from the National Alzheimer's Coordinating Center (NACC) (n = 5,073, 158 APOE-e4/e4), the Rotterdam Study (n = 6,399, 156 APOE-e4/e4), the Framingham Heart Study (n = 4,078, 67 APOE-e4/e4), and the Sacramento Area Latino Study on Aging (SALSA) (n = 1,294, 11 APOE-e4/e4). We computed stratified cumulative incidence curves by age (60-64, 65-69, 70-75 y) and APOE-e4 dose, adjusting for the competing risk of mortality, and determined risk of MCI and/or dementia by genotype and baseline age. We also used subdistribution hazard regression to model relative hazard based on age, APOE genotype, sex, education, family history of dementia, vascular risk, subjective memory concerns, and baseline cognitive performance. The four cohorts varied considerably in age, education, ethnicity/race, and APOE-e4 allele frequency. Overall, cumulative incidence was uniformly higher in NACC than in the population-based cohorts. Among APOE-e4/e4 individuals, 5-y cumulative incidence was as follows: in the 60-64-y age stratum, it ranged from 0% to 5.88% in the three population-based cohorts versus 23.06% in NACC; in the 65-69-y age stratum, from 9.42% to 10.39% versus 34.62%; and in the 70-75-y age stratum, from 18.64% to 33.33% versus 38.34%. Five-year incidence of dementia was negligible except for APOE-e4/e4 individuals and those over 70 y. Lifetime incidence (to age 80-85 y) of MCI or dementia for the APOE-e4/e4 individuals in the long-term Framingham and Rotterdam cohorts was 34.69%-38.45% at age 60-64 y, 30.76%-40.26% at 65-69 y, and 33.3%-35.17% at 70-75 y. Confidence limits for these estimates are often wide, particularly for APOE-e4/e4 individuals and for the dementia outcome at 5 y. In regression models, APOE-e4 dose and age both consistently increased risk, as did lower education, subjective memory concerns, poorer baseline cognitive performance, and family history of dementia. We discuss several limitations of the study, including the small numbers of APOE-e4/e4 individuals, missing data and differential dropout, limited ethnic and racial diversity, and differences in definitions of exposure and outcome variables.
Estimates of the absolute risk of MCI or dementia, particularly over short time intervals, are sensitive to sampling and a variety of methodological factors. Nonetheless, such estimates were fairly consistent across the population-based cohorts, and lower than those from a convenience cohort and those estimated in prior studies-with implications for informed consent and design for clinical trials targeting high-risk individuals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background The treatment of chronic hypersensitivity pneumonitis (cHP) often includes systemic oral corticosteroids, but the optimal pharmacologic management remains unclear. The morbidity associated ...with prednisone has motivated the search for alternative therapies. We aimed to determine the effect of treatment with mycophenolate mofetil (MMF) or azathioprine (AZA) on lung function in patients with cHP. Methods Patients with cHP treated with either MMF or AZA were retrospectively identified from four interstitial lung disease centers. Change in lung function before and after treatment initiation was analyzed using linear mixed-effects modeling (LMM), adjusting for age, sex, smoking history, and prednisone use. Results Seventy patients were included: 51 were treated with MMF and 19 with AZA. Median follow-up after treatment initiation was 11 months. Prior to treatment initiation, FVC and diffusion capacity of the lung for carbon monoxide (D lco ) % predicted were declining at a mean rate of 0.12% ( P < .001) and 0.10% ( P < .001) per month, respectively. Treatment with either MMF or AZA was not associated with improved FVC (0.5% at 1 year; P = .46) but was associated with a statistically significant improvement in D lco of 4.2% ( P < .001) after 1 year of treatment. Results were similar in the subgroup of patients treated with MMF for 1 year; the FVC increased nonsignificantly by 1.3% ( P = .103) and D lco increased by 3.9% ( P < .001). Conclusions Treatment with MMF or AZA is associated with improvements in D lco in patients with cHP. Prospective randomized trials are needed to validate their effectiveness for cHP.
We probe the indistinguishability of photons emitted by a semiconductor quantum dot (QD) via time- and temperature-dependent two-photon interference (TPI) experiments. An increase in temporal ...separation between consecutive photon emission events reveals a decrease in TPI visibility on a nanosecond time scale, theoretically described by a non-Markovian noise process in agreement with fluctuating charge traps in the QD's vicinity. Phonon-induced pure dephasing results in a decrease in TPI visibility from (96±4)% at 10 K to a vanishing visibility at 40 K. In contrast to Michelson-type measurements, our experiments provide direct access to the time-dependent coherence of a quantum emitter on a nanosecond time scale.
Collagen-producing cells maintain the complex architecture of the lung and drive pathologic scarring in pulmonary fibrosis. Here we perform single-cell RNA-sequencing to identify all ...collagen-producing cells in normal and fibrotic lungs. We characterize multiple collagen-producing subpopulations with distinct anatomical localizations in different compartments of murine lungs. One subpopulation, characterized by expression of Cthrc1 (collagen triple helix repeat containing 1), emerges in fibrotic lungs and expresses the highest levels of collagens. Single-cell RNA-sequencing of human lungs, including those from idiopathic pulmonary fibrosis and scleroderma patients, demonstrate similar heterogeneity and CTHRC1-expressing fibroblasts present uniquely in fibrotic lungs. Immunostaining and in situ hybridization show that these cells are concentrated within fibroblastic foci. We purify collagen-producing subpopulations and find disease-relevant phenotypes of Cthrc1-expressing fibroblasts in in vitro and adoptive transfer experiments. Our atlas of collagen-producing cells provides a roadmap for studying the roles of these unique populations in homeostasis and pathologic fibrosis.
PDF
