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As is the case for solid tumors, treatment paradigms have shifted from non-specific chemotherapeutic agents towards novel targeted drugs in the treatment of patients with multiple myeloma (MM). Currently, multiple targeted therapies are available to treat patients augmenting the arsenal of modalities which also includes chemotherapy, immunotherapy, radiation therapy, hematopoietic stem cell transplantation (HSCST) and chimeric antigen T-cell therapy (CAR-T). These novel, targeted agents have dramatically increased optimism for patients, who may now be treated over many years with successive regimens. As fortunate as we are to have these new therapies available for our patients, this advantage is juxtaposed with the challenges involved with delivering them safely. While each class of agents has demonstrated efficacy, in terms of response rates and survival, they also exert class effects which pose risks for toxicity. In addition, newer generation agents within the classes often have slightly different toxicity profiles than did their predecessors. These factors must be addressed, and their risks mitigated by the multidisciplinary team. This review presents a summary of the evolution of drug development for MM. For each targeted agent, the efficacy data from pivotal trials and highlights of the risks that were demonstrated in trials, as well as during post-marketing surveillance, are presented. Specific risks associated with agents within the classes, that are not shared with all new class members, are described. A table presenting these potential risks, with recommended nursing actions to mitigate toxicity, is provided as a quick reference that nurses may use during the planning, and provision, of patient care.

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Climatic change is expected to affect individual life histories and population dynamics, potentially increasing vulnerability to extinction. The importance of genetic diversity has been highlighted for adaptation and population persistence. However, whether responses of life-history traits to a given environmental condition depend on the genetic characteristics of a population remains elusive. Here we tested this hypothesis in the lizard Zootoca vivipara by simultaneously manipulating habitat humidity, a major climatic predictor of Zootoca's distribution, and adult male color morph frequency, a trait with genome-wide linkage. Interactive effects of humidity and morph frequency had immediate effects on growth and body condition of juveniles and yearlings, as well as on adult survival, and delayed effects on offspring size. In yearlings, higher humidity led to larger female body size and lower humidity led to higher male compared to female survival. In juveniles and yearlings, some treatment effects were compensated over time. The results show that individual responses to environmental conditions depend on the population's color morph frequency, age class, and sex and that these affect intra- and inter-age class competition. Moreover, humidity affected the competitive environment rather than imposing trait-based selection on specific color morphs. This indicates that species' responses to changing environments (e.g., to climate change) are highly complex and difficult to accurately reconstruct and predict without information on the genetic characteristics and demographic structure of populations.

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BACKGROUND: Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. PATIENTS AND METHODS: Adults with vascular endothelial growth factor-refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. RESULTS: In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. CONCLUSION: Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.

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Naming and word-retrieval deficits, which are common characteristics of primary progressive aphasia (PPA), differentially affect production across word classes (e.g., nouns, verbs) in some patients. Individuals with the agrammatic variant (PPA-G) often show greater difficulty producing verbs whereas those with the semantic variant (PPA-S) show greater noun deficits and those with logopenic PPA (PPA-L) evince no clear-cut differences in production of the two word classes. To determine the source of these production patterns, the present study examined word-finding pauses as conditioned by lexical variables (i.e., word class, frequency, length) in narrative speech samples of individuals with PPA-S (n=12), PPA-G (n=12), PPA-L (n=11), and cognitively healthy controls (n=12). We also examined the relation between pause distribution and cortical atrophy (i.e., cortical thickness) in nine left hemisphere regions of interest (ROIs) linked to word production. Results showed higher overall pause rates for PPA compared to unimpaired controls; however, greater naming severity was not associated with increased pause rate. Across all groups, more pauses were produced before lower vs. higher frequency words, with no independent effects of word length after controlling for frequency. With regard to word class, the PPA-L group showed a higher rate of pauses prior to production of nouns compared to verbs, consistent with noun-retrieval deficits arising at the lemma level of word production. Those with PPA-G and PPA-S, like controls, produced similar pause rates across word classes; however, lexical simplification (i.e., production of higher-frequency and/or shorter words) was evident in the more-impaired word class: nouns for PPA-S and verbs for PPA-G. These patterns are consistent with conceptual and/or lemma-level impairments for PPA-S, predominantly affecting objects/nouns, and a lemma-level verb-retrieval deficit for PPA-G, with a concomitant impairment in phonological encoding and articulation affecting overall pause rates. The greater tendency to pause before nouns was correlated with atrophy in the left precentral gyrus, inferior frontal gyrus and inferior parietal lobule, whereas the greater tendency to pause before less frequent and longer words was associated with atrophy in left precentral and inferior parietal regions.

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There have been over 100 randomized clinical trials (RCTs) of diverse regimens of antiretroviral therapy for treatment-naïve human immunodeficiency virus-positive patients. A further 400 systematic reviews and meta-analyses are informed by these trials. There are, however, difficulties in using systematic reviews and meta-analyses of this clinical evidence to inform guidelines and clinical practice. Several issues can make the interpretation of comparative effectiveness challenging. In this article, we review the key challenges in interpreting multiple trials in this population. We specifically examine the network geometry of the clinical trial comparisons, the predominance of non-inferiority trial designs, issues related to potential class effects, heterogeneous documentation of adverse events, and a relative lack of RCTs that reflect specific current clinical guideline recommendations. We conclude with recommendations for future clinical trials and meta-analyses.

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Angiotensin II (Ang II) evokes inflammatory responses and plays a central role in atherosclerosis mediated by Ang II type 1 (AT1) receptor. AT1 receptor blockers (ARBs) prevent the diverse effects of Ang II. Unique molecule-specific, or off-target effects of ARBs are due to their slightly different structures, although all ARBs have common, or class, effects. In nonsignificant coronary stenotic lesions, it is important that we use aggressive medical treatments using ARBs in addition to statins and oral hypoglycemic agents, to induce the regression and stabilization of coronary plaque. This review focuses on current evidence regarding the molecule-specific effects of ARB olmesartan to prevent the increase in coronary atheroma volume.

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Therapeutic substitutions are common at the level of ministries of health, clinicians, and pharmacy dispensaries. Guidance in determining whether drugs offer similar risk-benefit profiles is limited. Those making decisions on therapeutic substitutions should be aware of potential biases that make differentiating therapeutic agents difficult. Readers should consider whether the biological mechanisms and doses are similar across agents, whether the evidence is sufficiently valid across agents, and whether the safety and therapeutic effects of each drug are similar. This article uses a problem-based format to address the biological mechanism, validity, and results of a scenario in which therapeutic substitutions may be considered.

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Este estudo mediu o efeito-escola no desempenho acadêmico dos alunos de sete escolas públicas que atendem a comunidades vizinhas relativamente homogêneas do ponto de vista socioeconômico. O efeito-escola foi mensurado através da identificação da parte do progresso dos alunos que pode ser atribuída às escolas. A pesquisa coletou dados longitudinais junto a todas as turmas de 5ª série do Ensino Fundamental no início e no final do ano letivo. Os alunos responderam a testes de Português (leitura) e Matemática e preencheram um questionário sobre suas características demográficas, socioeconômicas e culturais, itens sobre o percurso escolar e hábitos de estudo. Também foram realizadas entrevistas com profissionais das escolas e com familiares dos alunos com o objetivo de contextualizar os resultados obtidos com os instrumentos quantitativos. Os resultados revelam que o efeito-escola se estrutura pela forma como as escolas organizam os alunos em turmas. A formação das turmas por nível de habilidade impacta não apenas o nível de desempenho dos alunos, mas também as diferenças nas taxas de progresso observadas durante o estudo. Os critérios de formação de turmas contribuem para que pequenas diferenças entre os alunos se transformem em grandes diferenças entre os grupos e acirrem a estratificação escolar de uma forma mais ampla.

This study measures the school effects on the achievement for fifth grade students of seven public schools, which serve homogeneous, in terms of their socioeconomic status, communities. The school effect is measured through a hierarchical linear model, which allows the separation of the learning of fifth grade students due to their schools practices from other sources of influence. The students included in this study were tested at the beginning and at the end of the school year. They answered a Portuguese language and a Mathematics test and filled a questionnaire with items on their demographic, socioeconomic and cultural characteristics. Additional items in the questionnaire captured the students' studying habits and their academic trajectory. Some parents and school staff were also interviewed in order to help the contextualization of the results, obtained with the achievement tests and questionnaires. The results show that the way the schools allocate students to classes has a large impact on student achievement. Using academic ability to allocate students to different classes impact not only the individual student achievement level, but also their corresponding learning rates. This class composition criterion contributes to transform small initial differences among students in large differences on their academic achievement, increasing therefore the school stratification.