The observation and analysis of intra-tumour heterogeneity (ITH), particularly in genomic studies, has advanced our understanding of the evolutionary forces that shape cancer growth and development. ...However, only a subset of the variation observed in a single tumour will have an impact on cancer evolution, highlighting the need to distinguish between functional and non-functional ITH. Emerging studies highlight a role for the cancer epigenome, transcriptome and immune microenvironment in functional ITH. Here, we consider the importance of both genetic and non-genetic ITH and their role in tumour evolution, and present the rationale for a broad research focus beyond the cancer genome. Systems-biology analytical approaches will be necessary to outline the scale and importance of functional ITH. By allowing a deeper understanding of tumour evolution this will, in time, encourage development of novel therapies and improve outcomes for patients.
Abstract
Objective
The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women.
Conclusions
Evidence from clinical trials and ...insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporosis. Patient preferences, data on adherence and persistence, and risks and benefits from the patient and provider perspectives were also considered in writing committee deliberations. A consensus by the Writing Committee members was achieved for four management principles: (i) The risk of future fractures in postmenopausal women should be determined using country-specific assessment tools to guide decision-making. (ii) Patient preferences should be incorporated into treatment planning. (iii) Nutritional and lifestyle interventions and fall prevention should accompany all pharmacologic regimens to reduce fracture risk. (iv) Multiple pharmacologic therapies are capable of reducing fracture rates in postmenopausal women at risk with acceptable risk-benefit and safety profiles.
Management of therapies for osteoporosis in postmenopausal women.
Summary Early childhood development programmes vary in coordination and quality, with inadequate and inequitable access, especially for children younger than 3 years. New estimates, based on proxy ...measures of stunting and poverty, indicate that 250 million children (43%) younger than 5 years in low-income and middle-income countries are at risk of not reaching their developmental potential. There is therefore an urgent need to increase multisectoral coverage of quality programming that incorporates health, nutrition, security and safety, responsive caregiving, and early learning. Equitable early childhood policies and programmes are crucial for meeting Sustainable Development Goals, and for children to develop the intellectual skills, creativity, and wellbeing required to become healthy and productive adults. In this paper, the first in a three part Series on early childhood development, we examine recent scientific progress and global commitments to early childhood development. Research, programmes, and policies have advanced substantially since 2000, with new neuroscientific evidence linking early adversity and nurturing care with brain development and function throughout the life course.
The development of cognitive and socioemotional skills early in life influences later health and well-being. Existing estimates of unmet developmental potential in low- and middle-income countries ...(LMICs) are based on either measures of physical growth or proxy measures such as poverty. In this paper we aim to directly estimate the number of children in LMICs who would be reported by their caregivers to show low cognitive and/or socioemotional development.
The present paper uses Early Childhood Development Index (ECDI) data collected between 2005 and 2015 from 99,222 3- and 4-y-old children living in 35 LMICs as part of the Multiple Indicator Cluster Survey (MICS) and Demographic and Health Surveys (DHS) programs. First, we estimate the prevalence of low cognitive and/or socioemotional ECDI scores within our MICS/DHS sample. Next, we test a series of ordinary least squares regression models predicting low ECDI scores across our MICS/DHS sample countries based on country-level data from the Human Development Index (HDI) and the Nutrition Impact Model Study. We use cross-validation to select the model with the best predictive validity. We then apply this model to all LMICs to generate country-level estimates of the prevalence of low ECDI scores globally, as well as confidence intervals around these estimates. In the pooled MICS and DHS sample, 14.6% of children had low ECDI scores in the cognitive domain, 26.2% had low socioemotional scores, and 36.8% performed poorly in either or both domains. Country-level prevalence of low cognitive and/or socioemotional scores on the ECDI was best represented by a model using the HDI as a predictor. Applying this model to all LMICs, we estimate that 80.8 million children ages 3 and 4 y (95% CI 48.1 million, 113.6 million) in LMICs experienced low cognitive and/or socioemotional development in 2010, with the largest number of affected children in sub-Saharan Africa (29.4.1 million; 43.8% of children ages 3 and 4 y), followed by South Asia (27.7 million; 37.7%) and the East Asia and Pacific region (15.1 million; 25.9%). Positive associations were found between low development scores and stunting, poverty, male sex, rural residence, and lack of cognitive stimulation. Additional research using more detailed developmental assessments across a larger number of LMICs is needed to address the limitations of the present study.
The number of children globally failing to reach their developmental potential remains large. Additional research is needed to identify the specific causes of poor developmental outcomes in diverse settings, as well as potential context-specific interventions that might promote children's early cognitive and socioemotional well-being.
Abstract
Objective
The objective is to provide an update of the 2019 Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline for the ...pharmacological management of osteoporosis in postmenopausal women using romosozumab.
Conclusions
We reviewed findings from the meta-analysis and primary clinical trials assessing the efficacy of romosozumab, a monoclonal antibody targeting sclerostin, for the prevention of fractures and concluded that this agent can be considered a treatment option for postmenopausal women at very high risk for osteoporotic fracture. The romosozumab label has a boxed warning, recommending careful consideration by the treating clinician as to cardiovascular risk profile in the individual woman who might receive this agent, since clinical trial data from an active comparator study show an imbalance in serious cardiovascular adverse events between romosozumab and alendronate.
Previous findings have been mixed regarding the relationship between maternal depressive symptoms and child cognitive development. The objective of this study was to systematically review relevant ...literature and to perform a meta-analysis.
Three electronic databases (PubMed, EMBASE, PsycINFO) were searched. Initial screening was conducted independently by two reviewers. Studies selected for detailed review were read in full and included based on a set of criteria. Data from selected studies were abstracted onto a standardized form. Meta-analysis using the inverse variance approach and random-effects models was conducted.
The univariate analysis of 14 studies revealed that maternal depressive symptoms are related to lower cognitive scores among children aged ⩽56 months (Cohen's d = -0.25, 95% CI -0.39 to -0.12). The synthesis of studies controlling for confounding variables showed that the mean cognitive score for children 6-8 weeks post-partum whose mothers had high depressive symptoms during the first few weeks postpartum was approximately 4.2 units lower on the Mental Developmental Index (MDI) of the Bayley Scales of Infant and Toddler Development (BSID) compared with children with non-symptomatic mothers (B̂ = -4.17, 95% CI -8.01 to -0.32).
The results indicated that maternal depressive symptoms are related to lower cognitive scores in early infancy, after adjusting for confounding factors. An integrated approach for supporting child cognitive development may include program efforts that promote maternal mental health in addition to family economic wellbeing, responsive caregiving, and child nutrition.
Renal tissue injury initiates inflammatory and fibrotic processes that occur to promote regeneration and repair. After renal injury, damaged tissue releases cytokines and chemokines, which stimulate ...activation and infiltration of inflammatory cells to the kidney. Normal tissue repair processes occur simultaneously with activation of myofibroblasts, collagen deposition, and wound healing responses; however, prolonged activation of pro-inflammatory and pro-fibrotic cell types causes excess extracellular matrix deposition. This review focuses on the physiological and pathophysiological roles of specialized cell types, cytokines/chemokines, and growth factors, and their implications in recovery or exacerbation of acute kidney injury.
Summary Background A 2007 study published in The Lancet estimated that approximately 219 million children aged younger than 5 years were exposed to stunting or extreme poverty in 2004. We updated the ...2004 estimates with the use of improved data and methods and generated estimates for 2010. Methods We used country-level prevalence of stunting in children younger than 5 years based on the 2006 Growth Standards proposed by WHO and poverty ratios from the World Bank to estimate children who were either stunted or lived in extreme poverty for 141 low-income and middle-income countries in 2004 and 2010. To avoid counting the same children twice, we excluded children jointly exposed to stunting and extreme poverty from children living in extreme poverty. To examine the robustness of estimates, we also used moderate poverty measures. Findings The 2007 study underestimated children at risk of poor development. The estimated number of children exposed to the two risk factors in low-income and middle-income countries decreased from 279·1 million (95% CI 250·4 million–307·4 million) in 2004 to 249·4 million (209·3 million–292·6 million) in 2010; prevalence of children at risk fell from 51% (95% CI 46–56) to 43% (36–51). The decline occurred in all income groups and regions with south Asia experiencing the largest drop. Sub-Saharan Africa had the highest prevalence in both years. These findings were robust to variations in poverty measures. Interpretation Progress has been made in reducing the number of children exposed to stunting or poverty between 2004 and 2010, but this is still not enough. Scaling up of effective interventions targeting the most vulnerable children is urgently needed. Funding National Institutes of Health, Bill & Melinda Gates Foundation, Hilton Foundation, and WHO.
Abstract
Bisphosphonates (BPs) are highly effective in treating osteoporosis and reducing hip, vertebral, and other fractures by as much as 50% to 70%. However, since 2006, atypical femur fractures ...(AFFs) emerged as potential side effects of BPs and other treatments. These fractures have unusual radiologic features and occur with little trauma. Public concern has led to a >50% decrease in BP usage. AFFs are rare: for each AFF, >1200 fractures, including 135 hip fractures, are prevented. Case definition criteria were updated by the American Society of Bone and Mineral Research in 2014. Many epidemiologic studies have been reported, and although methodologically challenging, generally support a BP-AFF association. However, the magnitude of the association between BPs and AFFs is uncertain: estimates of relative risk for AFFs among BP users vs nonusers range from 1 to 65 with a meta-analysis estimate of 1.7. Although mechanistic studies have proposed several hypotheses explaining how BPs might decrease bone strength, AFF pathogenesis remains uncertain and cannot explain the paradox of efficacy of reduction of common fractures while increasing risk for rare fractures at one site. There are several consistent risk factors, including Asian race (in North America), femoral bowing, and glucocorticoid use, whereas others remain unclear. Consensus is emerging about strategies to prevent AFFs in BP users (including drug holidays after 5 years' use in some patients). In conclusion, AFFs can be devastating, but even under the most pessimistic assumptions, the benefit/risk ratio is highly positive for BPs, particularly during 3 to 5 years of use. As understanding of AFFs increases, it is becoming increasingly possible to maximize BP benefits while minimizing AFF risk.
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