To summarise the available evidence relating to the diagnosis, epidemiology, burden, outcome assessment and treatment of foot and ankle osteoarthritis (OA) and to develop an agenda to guide future ...research.
Members of the International Foot and Ankle Osteoarthritis Consortium compiled a narrative summary of the literature which formed the basis of an interactive discussion at the Osteoarthritis Research Society International World Congress in 2021, during which a list of 24 research agenda items were generated. Following the meeting, delegates were asked to rank the research agenda items on a 0 to 100 visual analogue rating scale (0 = not at all important to 100 = extremely important). Items scoring a mean of 70 or above were selected for inclusion.
Of the 45 delegates who attended the meeting, 31 contributed to the agenda item scoring. Nineteen research agenda items met the required threshold: three related to diagnosis, four to epidemiology, four to burden, three to outcome assessment and five to treatment.
Key knowledge gaps related to foot and ankle OA were identified, and a comprehensive agenda to guide future research planning was developed. Implementation of this agenda will assist in improving the understanding and clinical management of this common and disabling, yet relatively overlooked condition.
Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in ...whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge.
Somatic mutations drive the development of cancer and may contribute to ageing and other diseases
. Despite their importance, the difficulty of detecting mutations that are only present in single ...cells or small clones has limited our knowledge of somatic mutagenesis to a minority of tissues. Here, to overcome these limitations, we developed nanorate sequencing (NanoSeq), a duplex sequencing protocol with error rates of less than five errors per billion base pairs in single DNA molecules from cell populations. This rate is two orders of magnitude lower than typical somatic mutation loads, enabling the study of somatic mutations in any tissue independently of clonality. We used this single-molecule sensitivity to study somatic mutations in non-dividing cells across several tissues, comparing stem cells to differentiated cells and studying mutagenesis in the absence of cell division. Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues. Together, our results suggest that mutational processes that are independent of cell division are important contributors to somatic mutagenesis. We anticipate that the ability to reliably detect mutations in single DNA molecules could transform our understanding of somatic mutagenesis and enable non-invasive studies on large-scale cohorts.
We report the draft genome of the black cottonwood tree, Populus trichocarpa. Integration of shotgun sequence assembly with genetic mapping enabled chromosome-scale reconstruction of the genome. More ...than 45,000 putative protein-coding genes were identified. Analysis of the assembled genome revealed a whole-genome duplication event; about 8000 pairs of duplicated genes from that event survived in the Populus genome. A second, older duplication event is indistinguishably coincident with the divergence of the Populus and Arabidopsis lineages. Nucleotide substitution, tandem gene duplication, and gross chromosomal rearrangement appear to proceed substantially more slowly in Populus than in ARABIDOPSIS: Populus has more protein-coding genes than Arabidopsis, ranging on average from 1.4 to 1.6 putative Populus homologs for each Arabidopsis gene. However, the relative frequency of protein domains in the two genomes is similar. Overrepresented exceptions in Populus include genes associated with lignocellulosic wall biosynthesis, meristem development, disease resistance, and metabolite transport.
To determine the spirometric-based prevalence of COPD across different regions in Canada and to evaluate the site heterogeneity of risk factors.
In this cross-sectional, population-based study, ...random samples of non-institutionalized adults aged ≥40 years were generated by random digit dialling. Participants answered an interviewer-administered questionnaire and performed spirometry before and after bronchodilator administration. COPD was defined as post-bronchodilator FEV
/FVC <0.70 (fixed ratio, FR) and as FEV
/FVC <5th percentile (lower limits of normal, LLN). Separate logistic regression models were used to compute the risk (adjusted odds ratio, aOR) for COPD. I
and Tau
analyses were used to evaluate heterogeneity.
Out of 5176 (95%) participants, 4893 (47% male with mean age 56.6 years (95% confidence interval, 56.0-57.2)) had spirometry that satisfied ATS criteria. The population prevalence of COPD was 16.2% (95% CI, 14.5-17.8) by FR and 11.2% (95% CI, 9.7-12.6) by LLN. Male predominance in prevalence was shown by FR but not by LLN criteria. Patient characteristics associated with an increased risk of COPD included: age (OR 1.56; 95% CI 1.33-1.84); history of physician-diagnosed asthma (OR 3.30; 95% CI 2.42-4.49); and childhood hospitalization for respiratory illness (OR 1.81; 95% CI 1.17-2.80). In terms of smoking-related risk factors, current smoking status had the highest odds ratio (OR 3.49; 95% CI 2.55-4.80). Variance in prevalence among sites was significantly reduced by adjusting for risk factors in Tau
analyses. Higher odds of exposure for each risk factor was found in more severe COPD, suggesting that a higher risk could be linked to the development of severe disease.
This study reports the population prevalence of COPD in nine urban cities which collectively represent the majority of the Canadian population and demonstrates that heterogeneity in prevalence among sites is substantially explained by variation in associated risk factors for COPD.
Within the last decade the study of phenology has taken on new importance because of its contribution to climate-change research. However, phenology data sets spanning many years are rare in the ...tropics, making it difficult to evaluate possible responses of tropical communities to climate change. Here we use two data sets (1970–1983 and 1990–2002) to describe the fruiting patterns of the tropical tree community in Kibale National Park, Uganda. To address variation in spatial patterns, we describe fruiting over 2–3 y among four sites each separated by 12–15 km. Presently, the Kibale region is receiving c. 300 mm more rain than it did at the start of the century, droughts are less frequent, the onset of the rainy season is earlier, and the average maximum monthly temperature is 3.5 °C hotter than it was 25 y ago. The 1990–2002 phenology data illustrated high temporal variability in the proportion of the populations fruiting. Interannual variation in community-wide fruit availability was also high; however, the proportion of trees that fruited has increased over the past 12+y. At the species level a variety of patterns were exhibited; however, a number of the most common species currently rarely fruit, and when they do, typically <4% of the individuals take part in fruiting events. Combining the data set from 1990 to 2002 with that from 1970 to 1983 for specific species again reveals an increase in the proportion of trees fruiting between 1990 and 2002; however, the proportion of the populations fruiting decreased during the earlier period. When one examines particular species over this whole period a variety of patterns are evident. For example, Pouteria altissima exhibited a relatively regular pattern of fruiting during the 1970s; however, it rarely fruited in the 1990s. Contrasting phenological patterns at four sites revealed that at the community level the fruiting patterns of only one of the six pair-wise site combinations were correlated. Relationships between rainfall and fruiting were variable among sites. Contrasting changes in fruiting patterns over the 30 y with differences among the four sites varying in rainfall, suggests that the changes observed in fruiting may be due to climate change. Responses to this climate change are likely complex and will vary among species. However, for some species, current conditions appear unsuitable for fruiting.
We present spectroscopic observations for a sample of 36 Herschel-SPIRE 250-500 mum selected galaxies (HSGs) at 2 > z < 5 from the Herschel Multi-tiered Extragalactic Survey. Redshifts are confirmed ...as part of a large redshift survey of Herschel-SPIRE-selected sources covering ~0.93 deg super(2) in six extragalactic legacy fields. Observations were taken with the Keck I Low Resolution Imaging Speedometer and the Keck II DEep Imaging Multi-Object Spectrograph. Precise astrometry, needed for spectroscopic follow-up, is determined by identification of counterparts at 24 mum or 1.4 GHz using a cross-identification likelihood matching method. We present both individual and composite rest-frame ultraviolet spectra and infrared spectral energy distributions. The contribution at z ~ 4 has a lower limit of 3 x 10 super(-3) M sub(middot in circle) yr super(-1) h3 Mpc super(-3), gap20% of the estimated total SFRD. This highlights the importance of extremely infrared-luminous galaxies with high SFRs to the buildup of stellar mass, even at the earliest epochs.
Glucocorticoid levels rise dramatically in late gestation to mature foetal organs in readiness for postnatal life. Immature heart function may compromise survival. Cardiomyocyte glucocorticoid ...receptor (GR) is required for the structural and functional maturation of the foetal heart in vivo, yet the molecular mechanisms are largely unknown. Here we asked if GR activation in foetal cardiomyocytes in vitro elicits similar maturational changes. We show that physiologically relevant glucocorticoid levels improve contractility of primary-mouse-foetal cardiomyocytes, promote Z-disc assembly and the appearance of mature myofibrils, and increase mitochondrial activity. Genes induced in vitro mimic those induced in vivo and include PGC-1α, a critical regulator of cardiac mitochondrial capacity. SiRNA-mediated abrogation of the glucocorticoid induction of PGC-1α in vitro abolished the effect of glucocorticoid on myofibril structure and mitochondrial oxygen consumption. Using RNA sequencing we identified a number of transcriptional regulators, including PGC-1α, induced as primary targets of GR in foetal cardiomyocytes. These data demonstrate that PGC-1α is a key mediator of glucocorticoid-induced maturation of foetal cardiomyocyte structure and identify other candidate transcriptional regulators that may play critical roles in the transition of the foetal to neonatal heart.
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