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From the Congo and the Mekong to the Seine and the Mississippi, Earth's rivers carve through landscapes before coursing into the world's oceans through estuaries and deltas. Their inexorable flow carries sediment and more, acting as lifeblood for a variety of ecosystems and communities. More than any other surface feature of Earth, rivers, estuaries, and deltas are vitally important to our economic and social well-being, and our management of them often sits at the sharp edge of today's most pressing environmental challenges. The World Atlas of Rivers, Estuaries, and Deltas takes readers on an unforgettable tour of these dynamic bodies of water, explaining how they function at each stage of their flow. Combining maps and graphics with informative essays and beautiful photos, this invaluable reference book will give you a new appreciation for the power that rivers, estuaries, and deltas wield. Features a wealth of colour photos, maps, and infographics. Brings together invaluable perspectives from leading experts. Describes the rich biodiversity associated with the world's rivers, estuaries, and deltas. Explains how rivers, estuaries, and deltas work, from river networks to deltaic floodplains, and sheds light on the erosion, movement, and deposition of sediment. Describes the anatomy of rivers, estuaries, and deltas, from channel geometry and river planforms to estuarine shape and delta morphology. Examines the ecology and ecosystems of rivers, estuaries, and deltas and how humans interact with these environments. Additional topics include damming, climate change, water use, pollution, resource management, and planetary health, as well as future perspectives on these vital landscapes.

Background: Radiation-related heart disease and lung cancer can occur following radiotherapy for breast cancer but the duration of any mortality risk is uncertain. Methods: Mortality ratios, by laterality of breast cancer, were estimated using Poisson regression for 558 871 women recorded with breast cancer during 1973–2008 in the Surveillance, Epidemiology and End Results (SEER) cancer registries and followed until 01 January 2009. Results: For women diagnosed with breast cancer during 1973–1982 and given radiotherapy shortly afterwards, the cardiac mortality ratios, left-sided vs right-sided, were 1.19 (1.03–1.38), 1.35 (1.05–1.73), 1.64 (1.26–2.14) and 1.90 (1.52–2.37) at <10, 10–14, 15–19 and 20+ years since diagnosis (2 p for trend: <0.001). The lung cancer mortality ratios, ipsilateral vs contralateral, in these women were 1.05 (0.57–1.94), 2.04 (1.28–3.23) and 3.87 (2.19–6.82) at <10, 10–19 and 20+ years, respectively, (2 p for trend: 0.002). For women irradiated during 1983–92 there was evidence of radiation-related mortality for lung cancer, but not for heart disease. For women irradiated since 1993 there is, as yet, little evidence of any radiation-related mortality. Conclusion: In this population, the radiation-related risks were larger in the third decade after exposure than during the first two decades.

Postmastectomy radiotherapy was shown in previous meta-analyses to reduce the risks of both recurrence and breast cancer mortality in all women with node-positive disease considered together. However, the benefit in women with only one to three positive lymph nodes is uncertain. We aimed to assess the effect of radiotherapy in these women after mastectomy and axillary dissection. We did a meta-analysis of individual data for 8135 women randomly assigned to treatment groups during 1964–86 in 22 trials of radiotherapy to the chest wall and regional lymph nodes after mastectomy and axillary surgery versus the same surgery but no radiotherapy. Follow-up lasted 10 years for recurrence and to Jan 1, 2009, for mortality. Analyses were stratified by trial, individual follow-up year, age at entry, and pathological nodal status. 3786 women had axillary dissection to at least level II and had zero, one to three, or four or more positive nodes. All were in trials in which radiotherapy included the chest wall, supraclavicular or axillary fossa (or both), and internal mammary chain. For 700 women with axillary dissection and no positive nodes, radiotherapy had no significant effect on locoregional recurrence (two-sided significance level [2p]>0·1), overall recurrence (rate ratio [RR], irradiated vs not, 1·06, 95% CI 0·76–1·48, 2p>0·1), or breast cancer mortality (RR 1·18, 95% CI 0·89–1·55, 2p>0·1). For 1314 women with axillary dissection and one to three positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·68, 95% CI 0·57–0·82, 2p=0·00006), and breast cancer mortality (RR 0·80, 95% CI 0·67–0·95, 2p=0·01). 1133 of these 1314 women were in trials in which systemic therapy (cyclophosphamide, methotrexate, and fluorouracil, or tamoxifen) was given in both trial groups and, for them, radiotherapy again reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·67, 95% CI 0·55–0·82, 2p=0·00009), and breast cancer mortality (RR 0·78, 95% CI 0·64–0·94, 2p=0·01). For 1772 women with axillary dissection and four or more positive nodes, radiotherapy reduced locoregional recurrence (2p<0·00001), overall recurrence (RR 0·79, 95% CI 0·69–0·90, 2p=0·0003), and breast cancer mortality (RR 0·87, 95% CI 0·77–0·99, 2p=0·04). After mastectomy and axillary dissection, radiotherapy reduced both recurrence and breast cancer mortality in the women with one to three positive lymph nodes in these trials even when systemic therapy was given. For today's women, who in many countries are at lower risk of recurrence, absolute gains might be smaller but proportional gains might be larger because of more effective radiotherapy. Cancer Research UK, British Heart Foundation, UK Medical Research Council.

The world’s deltas are at risk of being drowned due to rising relative sea levels as a result of climate change, decreasing supplies of fluvial sediment, and human responses to these changes. This paper analyses how delta morphology evolves over multi-decadal timescales under environmental change using a process-based model. Model simulations over 10² years are used to explore the influence of three key classes of environmental change, both individually and in combination: (i) varying combinations of fluvial water and sediment discharges; (ii) varying rates of relative sea-level rise; and (iii) selected human interventions within the delta, comprising polder-dykes and cross-dams. The results indicate that tidal asymmetry and rate of sediment supply together affect residual flows and delta morphodynamics (indicated by sub-aerial delta area, rates of progradation and aggradation). When individual drivers of change act in combination, delta building processes such as the distribution of sediment flux, aggradation, and progradation are disrupted by the presence of isolated polder-dykes or cross-dams. This suggests that such interventions, unless undertaken at a very large scale, can lead to unsustainable delta building processes. Our findings can inform management choices in real-world tidally-influenced deltas, while the methodology can provide insights into other dynamic morphological systems.

Many of the world’s major river deltas face a sustainability crisis, as they come under threat of increases in salinity and the extent of tidal zones forced by combinations of sea-level rise, changes in river discharge and channel geometry. The relative contribution of these factors to future increases in tidal extent remains unconstrained, with most prior work emphasising the role of climate-driven sea-level rise. Here we use new field data from the Mekong delta to measure variations of river discharge and changes of channel geometry, and project them into the future. We combine these with projections of future sea-level rise into a 2D hydrodynamic numerical model and quantify the influence of the different driving factors on future tidal extension into the delta. We show that within the next two decades, tidal extension into the Mekong delta will increase by up to 56 km due to channel deepening (92%), dominantly driven by anthropogenic sediment starvation. Furthermore, even under strong mitigation scenarios, sediment starvation still drives a long-term commitment to future tidal extension. Specifically, by 2098 eustatically rising sea-levels are predicted to contribute only modestly to the projected extension. These findings demonstrate the urgent need for policy makers to adopt evidence-based measures to reverse negative sediment budgets that drive tidal extension into sediment starved deltas.

Gravity currents are the primary means by which sediments, solutes and heat are transported across the ocean-floor. Existing theory of gravity current flow employs a statistically-stable model of turbulent diffusion that has been extant since the 1960s. Here we present the first set of detailed spatial data from a gravity current over a rough seafloor that demonstrate that this existing paradigm is not universal. Specifically, in contrast to predictions from turbulent diffusion theory, self-sharpened velocity and concentration profiles and a stable barrier to mixing are observed. Our new observations are explained by statistically-unstable mixing and self-sharpening, by boundary-induced internal gravity waves; as predicted by recent advances in fluid dynamics. Self-sharpening helps explain phenomena such as ultra-long runout of gravity currents and restricted growth of bedforms, and highlights increased geohazard risk to marine infrastructure. These processes likely have broader application, for example to wave-turbulence interaction, and mixing processes in environmental flows. The current paradigm of material transport across the ocean-floor by gravity currents, is of turbulent flows with mixing processes analogous to rivers. However, uniquely high-resolution field data demonstrate that this paradigm is flawed and that gravity currents are analogous to self-organised atmospheric jets.

After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. We undertook a meta-analysis of individual patient data for 10 801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease. Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7–17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6–6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2–17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8–5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (10–19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1–12·5), 1·1% (–2·0 to 4·2), and 0·1% (–7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5–27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8–15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease. After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made. Cancer Research UK, British Heart Foundation, and UK Medical Research Council.

Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44 000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18 000); and polychemotherapy versus no chemotherapy (n=32 000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. Cancer Research UK; British Heart Foundation; UK Medical Research Council.

Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the encapsulated cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable cells with minimal cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10-15 letters, equivalent to two- to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using encapsulated cell implants may have application beyond disease caused by genetic mutations.

Proper evaluation of the performance of artificial intelligence techniques in the analysis of digitized medical images is paramount for the adoption of such techniques by the medical community and regulatory agencies. To compare several cross-validation (CV) approaches to evaluate the performance of a classifier for automatic grading of prostate cancer in digitized histopathologic images and compare the performance of the classifier when trained using data from 1 expert and multiple experts. This quality improvement study used tissue microarray data (333 cores) from 231 patients who underwent radical prostatectomy at the Vancouver General Hospital between June 27, 1997, and June 7, 2011. Digitized images of tissue cores were annotated by 6 pathologists for 4 classes (benign and Gleason grades 3, 4, and 5) between December 12, 2016, and October 5, 2017. Patches of 192 µm2 were extracted from these images. There was no overlap between patches. A deep learning classifier based on convolutional neural networks was trained to predict a class label from among the 4 classes (benign and Gleason grades 3, 4, and 5) for each image patch. The classification performance was evaluated in leave-patches-out CV, leave-cores-out CV, and leave-patients-out 20-fold CV. The analysis was performed between November 15, 2018, and January 1, 2019. The classifier performance was evaluated by its accuracy, sensitivity, and specificity in detection of cancer (benign vs cancer) and in low-grade vs high-grade differentiation (Gleason grade 3 vs grades 4-5). The statistical significance analysis was performed using the McNemar test. The agreement level between pathologists and the classifier was quantified using a quadratic-weighted κ statistic. On 333 tissue microarray cores from 231 participants with prostate cancer (mean [SD] age, 63.2 [6.3] years), 20-fold leave-patches-out CV resulted in mean (SD) accuracy of 97.8% (1.2%), sensitivity of 98.5% (1.0%), and specificity of 97.5% (1.2%) for classifying benign patches vs cancerous patches. By contrast, 20-fold leave-patients-out CV resulted in mean (SD) accuracy of 85.8% (4.3%), sensitivity of 86.3% (4.1%), and specificity of 85.5% (7.2%). Similarly, 20-fold leave-cores-out CV resulted in mean (SD) accuracy of 86.7% (3.7%), sensitivity of 87.2% (4.0%), and specificity of 87.7% (5.5%). Results of McNemar tests showed that the leave-patches-out CV accuracy, sensitivity, and specificity were significantly higher than those for both leave-patients-out CV and leave-cores-out CV. Similar results were observed for classifying low-grade cancer vs high-grade cancer. When trained on a single expert, the overall agreement in grading between pathologists and the classifier ranged from 0.38 to 0.58; when trained using the majority vote among all experts, it was 0.60. Results of this study suggest that in prostate cancer classification from histopathologic images, patch-wise CV and single-expert training and evaluation may lead to a biased estimation of classifier's performance. To allow reproducibility and facilitate comparison between automatic classification methods, studies in the field should evaluate their performance using patient-based CV and multiexpert data. Some of these conclusions may be generalizable to other histopathologic applications and to other applications of machine learning in medicine.