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\"Between 1850 and 1880, Impressionist landscape painting and early forms of photography flourished within the arts in France. In the context of massive social and political change that also marked this era, painters and photographers composed competing visions of France as modern and industrialized or as rural and anti-modern. Impressionist France explores the resonances between landscape art and national identity as reflected in the paintings and photographs made during this period, examining and illustrating in particular the works of key artists such as âEdouard Baldus, Gustave Le Gray, the Bisson Freres, âEdouard Manet, Jean-Franًcois Millet, Claude Monet, Charles Negre, and Camille Pissarro. This ambitious premise focuses on the whole of France, exploring the relationship between landscape art and the notion of French nationhood across the country's varied and spectacular landscapes in seven geographical sections and four scholarly essays, which provide new information regarding the production and impact of French Impressionism. \"-- Provided by publisher.

ObjectivesLength-for-age z-scores (LAZ) and stunting prevalence (%LAZ <–2) are commonly used to quantify linear growth faltering in young children in low- and middle-income countries (LMICs). The Healthy Birth, Growth and Development knowledge integration (HBGDki) consortium described postnatal linear growth faltering using LAZ-by-age trajectory modelling and child-level LAZ threshold-crossing events, including incident stunting onset (first occurrence of LAZ <–2) and stunting reversal (LAZ rising from <–2 to ≥–2). Using simulations, we assessed the suitability of these LAZ threshold-crossing metrics for characterising linear growth faltering in LMICs.MethodsWe simulated a synthetic cohort with a harmonically downward-shifting LAZ trajectory from birth to 24 months of age, with mean LAZs similar to the HBGDki pooled South Asian cohorts, and without any input parameters intended to differentially affect individuals’ growth across the height distribution or at different ages. We compared HBGDki empirical estimates of age interval-specific frequencies of incident stunting onset and stunting reversal with those from the synthetic cohort. Using synthetic cohorts, we examined how estimates of incident onset and reversal were affected by missing data, magnitude of the whole-population shift in the LAZ distribution and strength of the between-time-point correlation. We also compared the 3–24 month pattern of linear growth faltering expressed as age-related trajectories of average growth delay (chronological age minus height–age), mean LAZ or stunting prevalence.ResultsEmpirical estimates of age interval-specific incident stunting onset and stunting reversal in the HBGDki cohorts were similar to those observed in a synthetic cohort. Variability in LAZ threshold-crossing event rates is explained by starting LAZ, between-time-point correlation and the magnitude of the whole-population shift in the LAZ distribution. Incident stunting onset is also affected by missing data in preceding intervals. Stunting reversal occurs due to within-child variability (ie, imperfect between-time-point correlation) in the absence of any other phenomena that cause stunted children to become non-stunted at a later age. The linear growth faltering pattern based on growth delay differed from corresponding age-related trajectories of mean LAZ or stunting prevalence.ConclusionsIn longitudinal studies of linear growth faltering in LMICs, LAZ threshold-crossing indicators are byproducts of whole-population shifts in LAZ and within-child variability and should be interpreted accordingly. Reporting incident stunting onset and reversal rates, or analyses in which children are grouped by the timing of LAZ threshold-crossing events, may detract from efforts to understand when and why nearly all children in LMICs grow more slowly than expected for their age. Since mean LAZ and stunting prevalence are unsuitable for quantifying the rate and timing of population-average postnatal linear growth faltering, growth delay is recommended for consideration as a preferred metric.

Height-age is the age at which growth-faltered children’s average observed height or length equals the median height or length of a child growth standard, corresponding to a length-for-age z-score (LAZ) of 0. In randomized controlled trials (RCTs) in low- and middle-income countries (LMICs), expression of linear growth outcomes using height-age may enhance the interpretability of intervention effects compared to conventional use of LAZ. Height-age can be used to derive the proportion of maximal benefit (PMB), whereby PMB = 0% indicates no effect and PMB = 100% indicates the intervention promoted growth at the rate expected for healthy children with the same starting height-age. In this proof-of-concept study, height-age and PMB were compared to LAZ in a meta-analysis of RCTs of small-quantity lipid-based nutrient supplements (SQ-LNS). Pooling across 15 trials in 10 LMICs, mean differences (MD; SQ-LNS minus control) in LAZ and height-age were 0.15 (95%CI: 0.12, 0.17) and 12 days (95%CI: 9, 14), respectively (N = 36,970). LAZ MD and height-age MD were highly correlated (rho = 0.74 overall and 0.94 upon exclusion of an outlier). The pooled PMB indicated that SQ-LNS achieves 11% of optimal growth potential (95% CI: [9.4, 12]; N = 19,768; 12 comparisons), but there was a substantial impact of between-trial heterogeneity (I 2  = 90%). In conclusion, the effect of SQ-LNS on linear growth can be alternatively expressed in terms of height-age instead of LAZ. The PMB may enhance the interpretability of effect estimates by quantifying the extent to which an intervention improves growth in relation to a biological threshold, but further research is required to establish its validity and usefulness for assessing and comparing intervention effectiveness.

Infant undernutrition, defined by length‐ and weight‐based indices, is common in low‐ and middle‐income countries (LMICs), but corresponding deficits in head size have received less attention. In a cohort of term newborns in Dhaka, Bangladesh, we compared the severity of deficits (vs. World Health Organization Growth Standards) in head circumference (HC), length and weight at birth and every 3 months until 2 years of age (n range across timepoints: 843–920). We estimated the mean and 25th, 50th and 75th percentiles of HC‐, length‐ and weight‐for‐age z‐scores (HCZ, LAZ and WAZ, respectively). Differences between HCZ and LAZ (or WAZ) were analyzed using paired t tests and quantile regression. We also derived HCZ using height‐age instead of chronological age at 3–24 months. Mean HCZ was significantly higher than mean LAZ and WAZ at birth, but HCZ was significantly lower than LAZ at 6, 9 and 12 months and the HCZ and LAZ deficits were similar from 15 to 24 months. Mean HCZ was lower than WAZ at all ages beyond birth. Patterns were broadly consistent at the 25th, 50th and 75th percentiles. The HCZ deficit remained evident when HC was standardized using height‐age at all ages beyond birth, indicating HC was reduced relative to body size. In conclusion, among term‐born children in Dhaka, HCs were smaller than international standards at all ages up to 2 years, and there was no evidence of postnatal head sparing. Consideration should be given to routine measurement of HC in population health surveys in LMICs. Term infants in Bangladesh had smaller head circumferences compared to international standards. In the postnatal period (3–24 months of age), average deficits in head circumference were more severe than expected based on body lengths, indicating a lack of head‐sparing in a setting where early childhood undernutrition is widespread. Summary In a Bangladeshi cohort of term infants, average head circumference (HC) z‐scores were closer to international norms than corresponding length and weight z‐scores at birth, suggesting possible foetal head sparing. Postnatal head sparing was not observed among children in Dhaka at any timepoint following birth. At 6, 9 and 12 months of age, the HC distribution was further below the international norm compared to the length and weight distributions. Analyses using height‐age rather than chronological age showed that postnatal HC deficits were more severe than expected given children's average height, at all timepoints following birth. The entire HC distribution was negatively displaced relative to the international standard at all ages, indicating that the head size deficit is a whole‐population condition, analogous to linear growth faltering. HC, like length and weight, should be considered for routine monitoring in LMIC settings where early childhood undernutrition is common.

Anthropogenic climate change is now in full swing, our global average temperature already having increased by 1°C from preindustrial levels. Many studies have documented individual impacts of the changing climate that are particular to species or regions, but individual impacts are accumulating and being amplified more broadly. Scheffers et al. review the set of impacts that have been observed across genes, species, and ecosystems to reveal a world already undergoing substantial change. Understanding the causes, consequences, and potential mitigation of these changes will be essential as we move forward into a warming world. Science , this issue p. 10.1126/science.aaf7671 Most ecological processes now show responses to anthropogenic climate change. In terrestrial, freshwater, and marine ecosystems, species are changing genetically, physiologically, morphologically, and phenologically and are shifting their distributions, which affects food webs and results in new interactions. Disruptions scale from the gene to the ecosystem and have documented consequences for people, including unpredictable fisheries and crop yields, loss of genetic diversity in wild crop varieties, and increasing impacts of pests and diseases. In addition to the more easily observed changes, such as shifts in flowering phenology, we argue that many hidden dynamics, such as genetic changes, are also taking place. Understanding shifts in ecological processes can guide human adaptation strategies. In addition to reducing greenhouse gases, climate action and policy must therefore focus equally on strategies that safeguard biodiversity and ecosystems.

Klebsiella pneumoniae is a major cause of opportunistic healthcare-associated infections, which are increasingly complicated by the presence of extended-spectrum beta-lactamases (ESBLs) and carbapenem resistance. We conducted a year-long prospective surveillance study of K. pneumoniae clinical isolates in hospital patients. Whole-genome sequence (WGS) data reveals a diverse pathogen population, including other species within the K. pneumoniae species complex (18%). Several infections were caused by K. variicola/K. pneumoniae hybrids, one of which shows evidence of nosocomial transmission. A wide range of antimicrobial resistance (AMR) phenotypes are observed, and diverse genetic mechanisms identified (mainly plasmid-borne genes). ESBLs are correlated with presence of other acquired AMR genes (median n  = 10). Bacterial genomic features associated with nosocomial onset are ESBLs (OR 2.34, p  = 0.015) and rhamnose-positive capsules (OR 3.12, p  < 0.001). Virulence plasmid-encoded features (aerobactin, hypermucoidy) are observed at low-prevalence (<3%), mostly in community-onset cases. WGS-confirmed nosocomial transmission is implicated in just 10% of cases, but strongly associated with ESBLs (OR 21, p  < 1 × 10 −11 ). We estimate 28% risk of onward nosocomial transmission for ESBL-positive strains vs 1.7% for ESBL-negative strains. These data indicate that K. pneumoniae infections in hospitalised patients are due largely to opportunistic infections with diverse strains, with an additional burden from nosocomially-transmitted AMR strains and community-acquired hypervirulent strains. Klebsiella pneumoniae is an opportunistic pathogen of increasing public health concern due to the prevalence of antimicrobial resistance. Here, the authors provide insight into the resistance profiles, bacterial genome features and virulence genes, in a year-long prospective study of K. pneumoniae clinical isolates.

Proteomic analysis of histones has shown that they are subject to a superabundance of acylations, which extend far beyond acetylation, to include: crotonylation, propionylation, butyrylation, malonylation, succinylation, β-hydroxybutyrylation and 2-hydroxyisobutyrylation. To date, much of the functional data has focussed on histone crotonylation which, similar to acetylation, has been associated with positive gene regulation and is added by the acyltransferase, p300. Although Sirtuins 1–3, along with HDAC3, have been shown to possess decrotonylase activity in vitro , there is relatively little known about the regulation of histone crotonylation in vivo . Here we show that Histone Deacetylase 1 and 2 (HDAC1/2), the catalytic core of numerous co-repressor complexes, are important histone decrotonylase enzymes. A ternary complex of HDAC1/CoREST1/LSD1 is able to hydrolyse both histone H3 Lys18-acetyl (H3K18ac) and H3 Lys18-crotonyl (H3K18cr) peptide substrates. Genetic deletion of HDAC1/2 in ES cells increases global levels of histone crotonylation and causes an 85% reduction in total decrotonylase activity. Furthermore, we mapped H3K18cr in cells using ChIP-seq, with and without HDAC1/2, and observed increased levels of crotonylation, which largely overlaps with H3K18ac in the vicinity of transcriptional start sites. Collectively, our data indicate that HDAC1/2 containing complexes are critical regulators of histone crotonylation in vivo .

In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the “normal” of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected. Genet Med 2013:15(7):565–574

BackgroundMicrobiome dysbiosis predisposes to colorectal cancer (CRC), but a population-based study of oral antibiotic exposure and risk patterns is lacking.ObjectiveTo assess the association between oral antibiotic use and CRC risk.DesignA matched case–control study (incident CRC cases and up to five matched controls) was performed using the Clinical Practice Research Datalink from 1989 to 2012.Results28 980 CRC cases and 137 077 controls were identified. Oral antibiotic use was associated with CRC risk, but effects differed by anatomical location. Antibiotic use increased the risk of colon cancer in a dose-dependent fashion (ptrend <0.001). The risk was observed after minimal use, and was greatest in the proximal colon and with antibiotics with anti-anaerobic activity. In contrast, an inverse association was detected between antibiotic use and rectal cancers (ptrend=0.003), particularly with length of antibiotic exposure >60 days (adjusted OR (aOR), 0.85, 95% CI 0.79 to 0.93) as compared with no antibiotic exposure. Penicillins, particularly ampicillin/amoxicillin increased the risk of colon cancer (aOR=1.09 (1.05 to 1.13)), whereas tetracyclines reduced the risk of rectal cancer (aOR=0.90 (0.84 to 0.97)). Significant interactions were detected between antibiotic use and tumour location (colon vs rectum, pinteraction<0.001; proximal colon versus distal colon, pinteraction=0.019). The antibiotic–cancer association was found for antibiotic exposure occurring >10 years before diagnosis (aOR=1.17 (1.06 to 1.31)).ConclusionOral antibiotic use is associated with an increased risk of colon cancer but a reduced risk of rectal cancer. This effect heterogeneity may suggest differences in gut microbiota and carcinogenesis mechanisms along the lower intestinal tract.

Patients' own gut microbiota were the major source of Klebsiella pneumoniae, but extended-spectrum β-lactamase strains were acquired in the referring hospital. This highlights the potential for rectal screening, and the importance of the wider hospital network, for local risk management. Abstract Background Klebsiella pneumoniae is a leading cause of extended-spectrum β-lactamase (ESBL)-producing hospital-associated infections, for which elderly patients are at increased risk. Methods We conducted a 1-year prospective cohort study, in which a third of patients admitted to 2 geriatric wards in a specialized hospital were recruited and screened for carriage of K. pneumoniae by microbiological culture. Clinical isolates were monitored via the hospital laboratory. Colonizing and clinical isolates were subjected to whole-genome sequencing and antimicrobial susceptibility testing. Results K. pneumoniae throat carriage prevalence was 4.1%, rectal carriage 10.8%, and ESBL carriage 1.7%, and the incidence of K. pneumoniae infection was 1.2%. The isolates were diverse, and most patients were colonized or infected with a unique phylogenetic lineage, with no evidence of transmission in the wards. ESBL strains carried blaCTX-M-15 and belonged to clones associated with hospital-acquired ESBL infections in other countries (sequence type [ST] 29, ST323, and ST340). One also carried the carbapenemase blaIMP-26. Genomic and epidemiological data provided evidence that ESBL strains were acquired in the referring hospital. Nanopore sequencing also identified strain-to-strain transmission of a blaCTX-M-15 FIBK/FIIK plasmid in the referring hospital. Conclusions The data suggest the major source of K. pneumoniae was the patient's own gut microbiome, but ESBL strains were acquired in the referring hospital. This highlights the importance of the wider hospital network to understanding K. pneumoniae risk and infection prevention. Rectal screening for ESBL organisms on admission to geriatric wards could help inform patient management and infection control in such facilities.