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Background Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. Methods Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks. Results Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory ( p  = 0.053) and motor subscales ( p  = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. Conclusion Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

How can teachers introduce Islam to students when daily media headlines can prejudice students' perception of the subject? Should Islam be taught differently in secular universities than in colleges with a clear faith-based mission? What are strategies for discussing Islam and violence without perpetuating stereotypes? The contributors ofTeaching Islamic Studies in the Age of ISIS, Islamophobia, and the Internetaddress these challenges head-on and consider approaches to Islamic studies pedagogy, Islamaphobia and violence, and suggestions for how to structure courses. These approaches acknowledge the particular challenges faced when teaching a topic that students might initially fear or distrust. Speaking from their own experience, they include examples of collaborative teaching models, reading and media suggestions, and ideas for group assignments that encourage deeper engagement and broader thinking. The contributors also share personal struggles when confronted with students (including Muslim students) and parents who suspected the courses might have ulterior motives. In an age of stereotypes and misrepresentations of Islam, this book offers a range of means by which teachers can encourage students to thoughtfully engage with the topic of Islam. 1. This book strikes at a core and defining principle of the university: to expose students to new and challenging ideas and to encourage them to confront these ideas in a fair and objective manner. 2. It provides feasible, specific advice and encourages a frank discussion of an important challenge facing many teachers. 3. Author Courtney M. Dorroll is a young academic at a very small liberal arts college in South Carolina. As such, she is alert to the particular challenges facing a target audience for this book: new academics looking for advice on how to teach a sensitive but important topic to inexperienced students in smaller communities.

Robustness to perturbation is a fundamental feature of complex organisms. Mutations are the raw material for evolution, yet robustness to their effects is required for species survival. The mechanisms that produce robustness are poorly understood. Nonlinearities are a ubiquitous feature of development that may link variation in development to phenotypic robustness. Here, we manipulate the gene dosage of a signaling molecule, Fgf8 , a critical regulator of vertebrate development. We demonstrate that variation in Fgf8 expression has a nonlinear relationship to phenotypic variation, predicting levels of robustness among genotypes. Differences in robustness are not due to gene expression variance or dysregulation, but emerge from the nonlinearity of the genotype–phenotype curve. In this instance, embedded features of development explain robustness differences. How such features vary in natural populations and relate to genetic variation are key questions for unraveling the origin and evolvability of this feature of organismal development. Developmental processes often involve nonlinearities, but the consequences for translating genotype to phenotype are not well characterized. Here, Green et al. vary Fgf8 signaling across allelic series of mice and show that phenotypic robustness in craniofacial shape is explained by a nonlinear effect of Fgf8 expression.

Prospective malaria public health interventions are initially tested for entomological impact using standardised experimental hut trials. In some cases, data are collated as aggregated counts of potential outcomes from mosquito feeding attempts given the presence of an insecticidal intervention. Comprehensive data i.e. full breakdowns of probable outcomes of mosquito feeding attempts, are more rarely available. Bayesian evidence synthesis is a framework that explicitly combines data sources to enable the joint estimation of parameters and their uncertainties. The aggregated and comprehensive data can be combined using an evidence synthesis approach to enhance our inference about the potential impact of vector control products across different settings over time. Aggregated and comprehensive data from a meta-analysis of the impact of Pirimiphos-methyl, an indoor residual spray (IRS) product active ingredient, used on wall surfaces to kill mosquitoes and reduce malaria transmission, were analysed using a series of statistical models to understand the benefits and limitations of each. Many more data are available in aggregated format (N = 23 datasets, 4 studies) relative to comprehensive format (N = 2 datasets, 1 study). The evidence synthesis model had the smallest uncertainty at predicting the probability of mosquitoes dying or surviving and blood-feeding. Generating odds ratios from the correlated Bernoulli random sample indicates that when mortality and blood-feeding are positively correlated, as exhibited in our data, the number of successfully fed mosquitoes will be under-estimated. Analysis of either dataset alone is problematic because aggregated data require an assumption of independence and there are few and variable data in the comprehensive format. We developed an approach to combine sources from trials to maximise the inference that can be made from such data and that is applicable to other systems. Bayesian evidence synthesis enables inference from multiple datasets simultaneously to give a more informative result and highlight conflicts between sources. Advantages and limitations of these models are discussed.

With large wildfires becoming more frequent 1 , 2 , we must rapidly learn how megafires impact biodiversity to prioritize mitigation and improve policy. A key challenge is to discover how interactions among fire-regime components, drought and land tenure shape wildfire impacts. The globally unprecedented 3 , 4 2019–2020 Australian megafires burnt more than 10 million hectares 5 , prompting major investment in biodiversity monitoring. Collated data include responses of more than 2,000 taxa, providing an unparalleled opportunity to quantify how megafires affect biodiversity. We reveal that the largest effects on plants and animals were in areas with frequent or recent past fires and within extensively burnt areas. Areas burnt at high severity, outside protected areas or under extreme drought also had larger effects. The effects included declines and increases after fire, with the largest responses in rainforests and by mammals. Our results implicate species interactions, dispersal and extent of in situ survival as mechanisms underlying fire responses. Building wildfire resilience into these ecosystems depends on reducing fire recurrence, including with rapid wildfire suppression in areas frequently burnt. Defending wet ecosystems, expanding protected areas and considering localized drought could also contribute. While these countermeasures can help mitigate the impacts of more frequent megafires, reversing anthropogenic climate change remains the urgent broad-scale solution. Data collected from more than 2,000 taxa provide an unparalleled opportunity to quantify how extreme wildfires affect biodiversity, revealing that the largest effects on plants and animals were in areas with frequent or recent past fires and within extensively burnt areas.

Drosophila melanogaster is one of the most well studied genetic model organisms; nonetheless, its genome still contains unannotated coding and non-coding genes, transcripts, exons and RNA editing sites. Full discovery and annotation are pre-requisites for understanding how the regulation of transcription, splicing and RNA editing directs the development of this complex organism. Here we used RNA-Seq, tiling microarrays and cDNA sequencing to explore the transcriptome in 30 distinct developmental stages. We identified 111,195 new elements, including thousands of genes, coding and non-coding transcripts, exons, splicing and editing events, and inferred protein isoforms that previously eluded discovery using established experimental, prediction and conservation-based approaches. These data substantially expand the number of known transcribed elements in the Drosophila genome and provide a high-resolution view of transcriptome dynamics throughout development. Elements of gene function Three papers in this issue of Nature report on the modENCODE initiative, which aims to characterize functional DNA elements in the fruitfly Drosophila melanogaster and the roundworm Caenorhabditis elegans . Kharchenko et al . present a genome-wide chromatin landscape of the fruitfly, based on 18 histone modifications. They describe nine prevalent chromatin states. Integrating these analyses with other data types reveals individual characteristics of different genomic elements. Graveley et al . have used RNA-Seq, tiling microarrays and cDNA sequencing to explore the transcriptome in 30 distinct developmental stages of the fruitfly. Among the results are scores of new genes, coding and non-coding transcripts, as well as splicing and editing events. Finally, Nègre et al . have produced a map of the regulatory part of the fruitfly genome, defining a vast array of putative regulatory elements, such as enhancers, promoters, insulators and silencers. As part of the modENCODE initiative, which aims to characterize functional DNA elements in D. melanogaster and C. elegans , this study uses RNA-Seq, tiling microarrays and cDNA sequencing to explore the transcriptome in 30 distinct developmental stages of the fruitfly. Among the results are scores of new genes, coding and non-coding transcripts, as well as splicing and editing events.

PurposeThis study aimed to investigate the relationship between self-reported food security and kidney stone formation.MethodsData were collected from the National Health and Nutrition Examination Survey (NHANES), a database representative of the United States population. Food security status was assessed using the US Household Food Security Survey Module: Six-Item Short Form. Characteristics of patients were compared using the Chi-square test and the student t-test. Multivariate logistic regression was performed using a multi-model approach.ResultsWe analyzed 6,800 NHANES survey respondents. 37.2% of respondents were categorized as having “low food security” (scores 2–4) and 24.0% having “very low food security” (scores 5–6). 8.4% of respondents had a history of kidney stones. We found that people with very low food security had a 42% increased likelihood of developing kidney stones compared to those with high or marginal food security, after controlling for race, age, and comorbidities (OR 1.42; 95% CI 1.01–1.99). Between the different food security groups, no significant differences were observed in age, race/ethnicity, body mass index, gout history, osteoporosis history, or coronary artery disease history. Lower food security was associated with slightly younger age (< 1 year difference, p = 0.001), higher poverty-income ratio (p = 0.001), and many comorbidities, including kidney stones (p = 0.007).ConclusionOur study provides evidence for an association between food access and the risk of kidney stone disease. Given these findings, food insecurity should be investigated as a modifiable risk factor for the development of kidney stone disease.

Our goal was to assess the use and perceptions of complementary and alternative medicine (CAM) for kidney stones among a diverse, urban population. This was a cross-sectional study of patients treated for kidney stones in the Bronx, NY. We assessed demographic information, personal history of kidney stones, as well as knowledge and use of CAM for kidney stones. Patient demographics and responses were analyzed using chi-squared, t tests, and binomial logistic regression. 113 patients were surveyed. 90% identified as non-white, of whom 58% indicated Hispanic, 46% Latinx, and 23% Black. 56% of patients were born outside the United States. 56% of patients had heard of CAM for kidney stones and 44% had used CAM for kidney stones. The most common CAM were fruits (N = 42, 84%). Recurrent stone formers were more likely than first-time stone formers to have heard of CAM (68 vs 44% p = 0.013) and to have used CAM (56 vs 30%, p = 0.008). Those identifying as Hispanic were more likely to have both heard of and tried CAM for kidney stones (p = 0.036 and 0.022, respectively) compared to non-Hispanic patients. CAM are commonly used among our diverse, urban patient population. While some remedies are high in citrate and alkali (i.e., lemon, cranberry), others are high in oxalate (i.e., beets) and could potentially contribute to stone formation. These findings underpin the importance that medical providers educate themselves on the CAM used in their specific patient populations and discussing use with patients. Providers should aim to identify and reconcile therapeutics that oppose goals of treatment.

Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1 , ABCA7 , INPP5D , and APOE ), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case–control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.