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\"This book presents the most effective instructional strategies for promoting vocabulary growth in the early grades, when the interdependence of word learning and oral language development is especially strong. The authors guide teachers in choosing the best materials and in fostering home-school connections, and share six key principles for building vocabulary. Included are guiding questions; text boxes connecting vocabulary to the Common Core State Standards; examples from real teachers; reproducible checklists, rubrics, and other tools; and an appendix of additional vocabulary resources. Purchasers get access to a Web page where they can download and print the reproducible materials in a convenient 8 1/2\" x 11\" size\"-- Provided by publisher.

The primary aim of this study was to explore the relationship between teachers' instruction and students' vocabulary and comprehension in grades 3-5. The secondary aim of this study was to investigate whether this relationship differed for English monolingual and Spanish-English bilingual students. To meet these aims, we observed and recorded reading/language arts instruction in 33 classrooms at three points during an academic year, and we assessed 274 students on vocabulary and comprehension at the beginning and end of the year. Using field notes and student utterances to understand the context, we coded teacher utterances (e.g., questions, comments, prompts) as vocabulary instruction, comprehension instruction, other instruction, or noninstruction. We then identified five types of vocabulary-related instruction and five types of comprehension-related instruction. Using latent difference modeling, we investigated how the frequency of different types of instruction was associated with change in students' vocabulary and comprehension across the school year. Teachers' instruction related to definitions, word relations, and morphosyntax was positively associated with change in vocabulary; teachers' instruction related to application across contexts and literal comprehension was negatively associated with change in vocabulary; and teachers' instruction related to inferential comprehension was positively associated with change in comprehension. The findings also revealed an interaction between language status and teachers' instruction, such that instruction that attended to comprehension strategies was associated with greater positive change in comprehension for bilingual (but not for monolingual) students.

The objective of this study was to investigate the re-emergence of a previously important crop pathogen in Europe, Puccinia graminis f.sp. tritici, causing wheat stem rust. The pathogen has been insignificant in Europe for more than 60 years, but since 2016 it has caused epidemics on both durum wheat and bread wheat in local areas in southern Europe, and additional outbreaks in Central- and West Europe. The prevalence of three distinct genotypes/races in many areas, Clade III-B (TTRTF), Clade IV-B (TKTTF) and Clade IV-F (TKKTF), suggested clonal reproduction and evolution by mutation within these. None of these genetic groups and races, which likely originated from exotic incursions, were detected in Europe prior to 2016. A fourth genetic group, Clade VIII, detected in Germany (2013), was observed in several years in Central- and East Europe. Tests of representative European wheat varieties with prevalent races revealed high level of susceptibility. In contrast, high diversity with respect to virulence and Simple Sequence Repeat (SSR) markers were detected in local populations on cereals and grasses in proximity to Berberis species in Spain and Sweden, indicating that the alternate host may return as functional component of the epidemiology of wheat stem rust in Europe. A geographically distant population from Omsk and Novosibirsk in western Siberia (Russia) also revealed high genetic diversity, but clearly different from current European populations. The presence of Sr31 -virulence in multiple and highly diverse races in local populations in Spain and Siberia stress that virulence may emerge independently when large geographical areas and time spans are considered and that Sr31 -virulence is not unique to Ug99. All isolates of the Spanish populations, collected from wheat, rye and grass species, were succesfully recovered on wheat, which underline the plasticity of host barriers within P. graminis . The study demonstrated successful alignment of two genotyping approaches and race phenotyping methodologies employed by different laboratories, which also allowed us to line up with previous European and international studies of wheat stem rust. Our results suggest new initiatives within disease surveillance, epidemiological research and resistance breeding to meet current and future challenges by wheat stem rust in Europe and beyond.

The CNS is ensheathed by the meninges and cerebrospinal fluid, and recent findings suggest that these CNS-associated border tissues have complex immunological functions. Unlike myeloid lineage cells, lymphocytes in border compartments have yet to be thoroughly characterized. Based on single-cell transcriptomics, we here identified a highly location-specific composition and expression profile of tissue-resident leukocytes in CNS parenchyma, pia-enriched subdural meninges, dura mater, choroid plexus and cerebrospinal fluid. The dura layer of the meninges contained a large population of B cells under homeostatic conditions in mice and rats. Murine dura B cells exhibited slow turnover and long-term tissue residency, and they matured in experimental neuroinflammation. The dura also contained B lineage progenitors at the pro-B cell stage typically not found outside of bone marrow, without direct influx from the periphery or the skull bone marrow. This identified the dura as an unexpected site of B cell residence and potentially of development in both homeostasis and neuroinflammation. The skull dura contains B cells and B lineage precursors under homeostatic conditions. These cells are long-term tissue resident and mature upon neuroinflammation. This identifies the dura as a site of B cell residence and potentially development.

Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. The 2007 criteria for HIV-associated neurocognitive disorders (HAND), sometimes called the Frascati criteria, can falsely classify over 20% of cognitively healthy individuals as having cognitive impairment. Minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which might not be appropriate for populations with diverse educational and socioeconomic backgrounds. Imprecise phenotyping of cognitive impairment can limit mechanistic research, biomarker discovery and treatment trials. Importantly, overestimation of cognitive impairment carries the risk of creating fear among people living with HIV and worsening stigma and discrimination towards these individuals. To address this issue, we established the International HIV-Cognition Working Group, which is globally representative and involves the community of people living with HIV. We reached consensus on six recommendations towards a new approach for diagnosis and classification of cognitive impairment in people living with HIV, intended to focus discussion and debate going forward. We propose the conceptual separation of HIV-associated brain injury — including active or pretreatment legacy damage — from other causes of brain injury occurring in people living with HIV. We suggest moving away from a quantitative neuropsychological approach towards an emphasis on clinical context. Our recommendations are intended to better represent the changing profile of cognitive impairment in people living with HIV in diverse global settings and to provide a clearer framework of classification for clinical management and research studies.Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. In this Consensus Statement, the International HIV-Cognition Working Group have outlined six recommendations towards a new approach, intended to better represent changes in the spectrum of HIV disease in the modern era of antiretroviral therapy.

Denisova Cave in southern Siberia is the type locality of the Denisovans, an archaic hominin group who were related to Neanderthals 1 – 4 . The dozen hominin remains recovered from the deposits also include Neanderthals 5 , 6 and the child of a Neanderthal and a Denisovan 7 , which suggests that Denisova Cave was a contact zone between these archaic hominins. However, uncertainties persist about the order in which these groups appeared at the site, the timing and environmental context of hominin occupation, and the association of particular hominin groups with archaeological assemblages 5 , 8 – 11 . Here we report the analysis of DNA from 728 sediment samples that were collected in a grid-like manner from layers dating to the Pleistocene epoch. We retrieved ancient faunal and hominin mitochondrial (mt)DNA from 685 and 175 samples, respectively. The earliest evidence for hominin mtDNA is of Denisovans, and is associated with early Middle Palaeolithic stone tools that were deposited approximately 250,000 to 170,000 years ago; Neanderthal mtDNA first appears towards the end of this period. We detect a turnover in the mtDNA of Denisovans that coincides with changes in the composition of faunal mtDNA, and evidence that Denisovans and Neanderthals occupied the site repeatedly—possibly until, or after, the onset of the Initial Upper Palaeolithic at least 45,000 years ago, when modern human mtDNA is first recorded in the sediments. Ancient mitochondrial DNA from sediments reveals the sequence of Denisovan, Neanderthal and faunal occupation of Denisova Cave, and evidence for the appearance of modern humans at least 45,000 years ago.

Microglia, the resident immune cells of the central nervous system (CNS), are derived from yolk-sac macrophages that populate the developing CNS during early embryonic development. Once established, the microglia population is self-maintained throughout life by local proliferation. As a scalable source of microglia-like cells (MGLs), we here present a forward programming protocol for their generation from human pluripotent stem cells (hPSCs). The transient overexpression of PU.1 and C/EBPβ in hPSCs led to a homogenous population of mature microglia within 16 d. MGLs met microglia characteristics on a morphological, transcriptional, and functional level. MGLs facilitated the investigation of a human tauopathy model in cortical neuron—microglia cocultures, revealing a secondary dystrophic microglia phenotype. Single-cell RNA sequencing of microglia integrated into hPSC-derived cortical brain organoids demonstrated a shift of microglia signatures toward a more-developmental in vivo—like phenotype, inducing intercellular interactions promoting neurogenesis and arborization. Taken together, our microglia forward programming platform represents a tool for both reductionist studies in monocultures and complex coculture systems, including 3D brain organoids for the study of cellular interactions in healthy or diseased environments.

Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1–25·7), 2-year overall survival was 63·8% (95% CI 53·3–72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1–66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43–1·26; p=0·26). Treatment-related grade 3–4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3–4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3–4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. Bristol-Myers Squibb.

Since the 1990s, Sweden has implemented aging-in-place policies increasing the share of older adults dependent on home care instead of residing in care homes. At the same time previous research has highlighted that individuals receive home care at a higher age than before. Consequently, services are provided for a shorter time before death, increasing reliance on family and kin as caregivers. Previous studies addressing how homecare is distributed rely primarily on small surveys and are often limited to specific regions. This study aims to ascertain how home care services are distributed regarding individual-level factors such as health status, living arrangements, availability of family, education, and socioeconomic position. To provide estimates that can be generalized to Sweden as a whole, we use register data for the entire Swedish population aged 65 + in 2016. The study's main findings are that home care recipients and the amount of care received are among the oldest old with severe co morbidities. Receiving home care is slightly more common among women, but only in the highest age groups. Childlessness and socioeconomic factors play a small role in who receives home care or not. Instead, the primary home care recipients are those older adults living alone who lack direct support from family members residing in the same household.

Cow’s milk allergy (CMA) is one of the most common presentations of food allergy seen in early childhood. It is also one of the most complex food allergies, being implicated in IgE-mediated food allergy as well as diverse manifestations of non-IgE-mediated food allergy. For example, gastrointestinal CMA may present as food protein induced enteropathy, enterocolitis or proctocolitis. Concerns regarding the early and timely diagnosis of CMA have been highlighted over the years. In response to these, guideline papers from the United Kingdom (UK), Australia, Europe, the Americas and the World Allergy Organisation have been published. The UK guideline, ‘Diagnosis and management of non-IgE-mediated cow’s milk allergy in infancy—a UK primary care practical guide’ was published in this journal in 2013. This Milk Allergy in Primary Care (MAP) guideline outlines in simple algorithmic form, both the varying presentations of cow’s milk allergy and also focuses on the practical management of the most common presentation, namely mild-to-moderate non-IgE-mediated allergy. Based on the international uptake of the MAP guideline, it became clear that there was a need for practical guidance beyond the UK. Consequently, this paper presents an international interpretation of the MAP guideline to help practitioners in primary care settings around the world. It incorporates further published UK guidance, feedback from UK healthcare professionals and affected families and, importantly, also international guidance and expertise.