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\"As noted in the preface, the underlying message of the original volume \"Children in Time and Place: Developmental and Historical Insights\" stressed the importance of recognizing that children's development is best understood when placed in a specific historical and life course developmental context. The current formulation updates this perspective by focusing more explicitly on the socio- cultural aspects as well\"-- Provided by publisher.

Technological and data sharing advances have led to a proliferation of high-resolution structural and functional maps of the brain. Modern neuroimaging research increasingly depends on identifying correspondences between the topographies of these maps; however, most standard methods for statistical inference fail to account for their spatial properties. Recently, multiple methods have been developed to generate null distributions that preserve the spatial autocorrelation of brain maps and yield more accurate statistical estimates. Here, we comprehensively assess the performance of ten published null frameworks in statistical analyses of neuroimaging data. To test the efficacy of these frameworks in situations with a known ground truth, we first apply them to a series of controlled simulations and examine the impact of data resolution and spatial autocorrelation on their family-wise error rates. Next, we use each framework with two empirical neuroimaging datasets, investigating their performance when testing (1) the correspondence between brain maps (e.g., correlating two activation maps) and (2) the spatial distribution of a feature within a partition (e.g., quantifying the specificity of an activation map within an intrinsic functional network). Finally, we investigate how differences in the implementation of these null models may impact their performance. In agreement with previous reports, we find that naive null models that do not preserve spatial autocorrelation consistently yield elevated false positive rates and unrealistically liberal statistical estimates. While spatially-constrained null models yielded more realistic, conservative estimates, even these frameworks suffer from inflated false positive rates and variable performance across analyses. Throughout our results, we observe minimal impact of parcellation and resolution on null model performance. Altogether, our findings highlight the need for continued development of statistically-rigorous methods for comparing brain maps. The present report provides a harmonised framework for benchmarking and comparing future advancements.

Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of ALK and ROS1 tyrosine kinases with broad coverage of ALK mutations. In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy. We aimed to analyse the overall and intracranial antitumour activity of lorlatinib in patients with ALK-positive, advanced non-small-cell lung cancer. In this phase 2 study, patients with histologically or cytologically ALK-positive or ROS1-positive, advanced, non-small-cell lung cancer, with or without CNS metastases, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and adequate end-organ function were eligible. Patients were enrolled into six different expansion cohorts (EXP1–6) on the basis of ALK and ROS1 status and previous therapy, and were given lorlatinib 100 mg orally once daily continuously in 21-day cycles. The primary endpoint was overall and intracranial tumour response by independent central review, assessed in pooled subgroups of ALK-positive patients. Analyses of activity and safety were based on the safety analysis set (ie, all patients who received at least one dose of lorlatinib) as assessed by independent central review. Patients with measurable CNS metastases at baseline by independent central review were included in the intracranial activity analyses. In this report, we present lorlatinib activity data for the ALK-positive patients (EXP1–5 only), and safety data for all treated patients (EXP1–6). This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Between Sept 15, 2015, and Oct 3, 2016, 276 patients were enrolled: 30 who were ALK positive and treatment naive (EXP1); 59 who were ALK positive and received previous crizotinib without (n=27; EXP2) or with (n=32; EXP3A) previous chemotherapy; 28 who were ALK positive and received one previous non-crizotinib ALK tyrosine kinase inhibitor, with or without chemotherapy (EXP3B); 112 who were ALK positive with two (n=66; EXP4) or three (n=46; EXP5) previous ALK tyrosine kinase inhibitors with or without chemotherapy; and 47 who were ROS1 positive with any previous treatment (EXP6). One patient in EXP4 died before receiving lorlatinib and was excluded from the safety analysis set. In treatment-naive patients (EXP1), an objective response was achieved in 27 (90·0%; 95% CI 73·5–97·9) of 30 patients. Three patients in EXP1 had measurable baseline CNS lesions per independent central review, and objective intracranial responses were observed in two (66·7%; 95% CI 9·4–99·2). In ALK-positive patients with at least one previous ALK tyrosine kinase inhibitor (EXP2–5), objective responses were achieved in 93 (47·0%; 39·9–54·2) of 198 patients and objective intracranial response in those with measurable baseline CNS lesions in 51 (63·0%; 51·5–73·4) of 81 patients. Objective response was achieved in 41 (69·5%; 95% CI 56·1–80·8) of 59 patients who had only received previous crizotinib (EXP2–3A), nine (32·1%; 15·9–52·4) of 28 patients with one previous non-crizotinib ALK tyrosine kinase inhibitor (EXP3B), and 43 (38·7%; 29·6–48·5) of 111 patients with two or more previous ALK tyrosine kinase inhibitors (EXP4–5). Objective intracranial response was achieved in 20 (87·0%; 95% CI 66·4–97·2) of 23 patients with measurable baseline CNS lesions in EXP2–3A, five (55·6%; 21·2–86·3) of nine patients in EXP3B, and 26 (53·1%; 38·3–67·5) of 49 patients in EXP4–5. The most common treatment-related adverse events across all patients were hypercholesterolaemia (224 [81%] of 275 patients overall and 43 [16%] grade 3–4) and hypertriglyceridaemia (166 [60%] overall and 43 [16%] grade 3–4). Serious treatment-related adverse events occurred in 19 (7%) of 275 patients and seven patients (3%) permanently discontinued treatment because of treatment-related adverse events. No treatment-related deaths were reported. Consistent with its broad ALK mutational coverage and CNS penetration, lorlatinib showed substantial overall and intracranial activity both in treatment-naive patients with ALK-positive non-small-cell lung cancer, and in those who had progressed on crizotinib, second-generation ALK tyrosine kinase inhibitors, or after up to three previous ALK tyrosine kinase inhibitors. Thus, lorlatinib could represent an effective treatment option for patients with ALK-positive non-small-cell lung cancer in first-line or subsequent therapy. Pfizer.

The era of personalized medicine for advanced-stage non-small-cell lung cancer (NSCLC) began when biomarker-based evidence of molecular pathway and/or oncogene addiction of the tumour became mandatory for the allocation of specific targeted therapies. More recently, the immunotherapy revolution, specifically, the development of immune-checkpoint inhibitors (ICIs), has dramatically altered the NSCLC treatment landscape. Herein, we compare and contrast the clinical development of immunotherapy and oncogene-directed therapy for NSCLC, focusing on the role of predictive biomarkers. Immunotherapy biomarkers are fundamentally different from oncogene biomarkers in that they are continuous rather than categorical (binary), spatially and temporally variable and reliant on multiple complex interactions rather than a single, dominant determinant. The performance of predictive biomarkers for ICIs might be improved by combining different markers to reduce the assumptive risks associated with each one. Novel combinations with chemotherapy and ICIs complicate biomarker discovery but do not decrease the value of the markers identified. Perfectly predictive biomarkers of benefit from immunotherapy are unlikely to be identified, although exclusionary biomarkers of minimal benefit or an unacceptable risk of toxicity might be feasible. The clinical adoption and applicability of such biomarkers might vary depending on line of treatment, the available therapeutic alternatives and health economic considerations.The advent of effective molecularly targeted treatments and immunotherapies for non-small-cell lung cancer (NSCLC) has greatly improved patient outcomes. Whereas most patients selected for treatment with molecularly targeted drugs derive benefits from these agents, benefit from immunotherapy is more difficult to predict. Herein, Camidge and colleagues compare and contrast predictive biomarkers for immunotherapy and targeted therapy of NSCLC to highlight considerations for biomarker development.

Concepts in Biology is a relatively brief introductory general biology text written for students with no previous science background. The authors strive to use the most accessible vocabulary and writing style possible while still maintaining scientific accuracy. The text covers all the main areas of study in biology from cells through ecosystems. Evolution and ecology coverage are combined in Part Four to emphasize the relationship between these two main subject areas. The new, 14th edition is the latest and most exciting revision of a respected introductory biology text written by authors who know how to reach students through engaging writing, interesting issues and applications, and accessible level. Instructors will appreciate the book's scientific accuracy, complete coverage and extensive supplement package.

The theoretical relationship between reproduction and body size has assumed that total mass relates directly to fecundity, regardless of the number of individuals involved. This assumption leads to fisheries management practices that suggest that one large female fish can be replaced by several smaller females. However, this assumption is incorrect. Barneche et al. show that larger females are far more productive than the same weight's worth of smaller females. Management practices that ignore the value of large females could contribute to unexplained declines seen in some fish stocks. Science , this issue p. 642 Reproduction does not scale linearly with body size in fish—bigger females produce many more offspring. Body size determines total reproductive-energy output. Most theories assume reproductive output is a fixed proportion of size, with respect to mass, but formal macroecological tests are lacking. Management based on that assumption risks underestimating the contribution of larger mothers to replenishment, hindering sustainable harvesting. We test this assumption in marine fishes with a phylogenetically controlled meta-analysis of the intraspecific mass scaling of reproductive-energy output. We show that larger mothers reproduce disproportionately more than smaller mothers in not only fecundity but also total reproductive energy. Our results reset much of the theory on how reproduction scales with size and suggest that larger mothers contribute disproportionately to population replenishment. Global change and overharvesting cause fish sizes to decline; our results provide quantitative estimates of how these declines affect fisheries and ecosystem-level productivity.

Alectinib—a highly selective, CNS-active, ALK inhibitor—showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib. We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB–IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment. Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3–7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36–60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment). Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib. F Hoffmann-La Roche.