Explore the vast range of titles available.

Sex and the Citizenis a multidisciplinary collection of essays that draws on current anxieties about \"legitimate\" sexual identities and practices across the Caribbean to explore both the impact of globalization and the legacy of the region's history of sexual exploitation during colonialism, slavery, and indentureship. Speaking from within but also challenging the assumptions of feminism, literary and cultural studies, and queer studies, this volume questions prevailing oppositions between the backward, homophobic nation-state and the laid-back, service-with-a-smile paradise or between giving in ignominiously to the autocratic demands of the global north and equating postcolonial sovereignty with a \"wholesome\" heterosexual citizenry. The contributors use parliamentary legislation, novels, film, and other texts to examine Martinique's relationship to France; the diasporic relationships between the Dominican Republic and New York City, between India and Trinidad, and between Mexico's capital city and its Caribbean coast; \"indigenous\" names for sexual practices and desires in Suriname and the Eastern Caribbean; and other topics. This volume will appeal to readers interested in how sex has become an important register for considerations of citizenship, personal and political autonomy, and identity in the Caribbean and the global south. Contributors: Vanessa Agard-Jones * Odile Cazenave * Michelle Cliff * Susan Dayal * Alison Donnell * Donette Francis * Carmen Gillespie* Rosamond S. King * Antonia MacDonald-Smythe * Tejaswini Niranjana * Evelyn O'Callaghan * Tracy Robinson * Patricia Saunders * Yasmin Tambiah * Omise'eke Natasha Tinsley * Rinaldo Walcott * M. S. Worrell

In this study, 1219 HIV-uninfected, heterosexual adults in Botswana were randomly assigned to tenofovir–emtricitabine (TDF–FTC) or placebo. The TDF–FTC group had a lower incidence of HIV infection but increased rates of side effects, including a significant loss of bone density. Biomedical strategies to prevent sexual transmission of human immunodeficiency virus (HIV) remain limited. 1 In animal models, preexposure prophylaxis with tenofovir disoproxil fumarate (TDF) or with the combination of TDF and emtricitabine (TDF–FTC) can prevent infections with HIV or hybrid simian–human immunodeficiency virus after vaginal or rectal challenge. 2 , 3 In humans, daily preexposure prophylaxis with TDF–FTC has been shown to reduce transmission of HIV by 44% among men who have sex with men 4 ; however, the findings from studies in heterosexual populations have been mixed. 5 – 8 Botswana has the world's second highest prevalence of HIV infection, estimated in 2008 to be . . .

Human saliva is clinically informative of both oral and general health. Since next generation shotgun sequencing (NGS) is now widely used to identify and quantify bacteria, we investigated the bacterial flora of saliva microbiomes of two healthy volunteers and five datasets from the Human Microbiome Project, along with a control dataset containing short NGS reads from bacterial species representative of the bacterial flora of human saliva. GENIUS, a system designed to identify and quantify bacterial species using unassembled short NGS reads was used to identify the bacterial species comprising the microbiomes of the saliva samples and datasets. Results, achieved within minutes and at greater than 90% accuracy, showed more than 175 bacterial species comprised the bacterial flora of human saliva, including bacteria known to be commensal human flora but also Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, and Gamma proteobacteria. Basic Local Alignment Search Tool (BLASTn) analysis in parallel, reported ca. five times more species than those actually comprising the in silico sample. Both GENIUS and BLAST analyses of saliva samples identified major genera comprising the bacterial flora of saliva, but GENIUS provided a more precise description of species composition, identifying to strain in most cases and delivered results at least 10,000 times faster. Therefore, GENIUS offers a facile and accurate system for identification and quantification of bacterial species and/or strains in metagenomic samples.

Background The standing broad jump (SBJ) is an excellent functional measure of explosive lower-body strength that is significantly related to health among children and adolescents. Objectives The aim of this study was to estimate national (country-level) and international (pooled global data) temporal trends in SBJ performance for children and adolescents, and to examine the relationships between national trends in SBJ performance and national trends in health-related and socioeconomic/demographic indicators. Methods Data were obtained from a systematic search of studies reporting temporal trends in SBJ performance for 9- to 17-year-olds, and by examining national fitness datasets. Sample-weighted regression models estimated trends at the study/dataset-country-sex-age level, with national and international trends estimated by a post-stratified population-weighting procedure. Pearson’s correlations quantified relationships between national trends in SBJ performance and national trends in health-related and socioeconomic/demographic indicators. Results Data from 34 studies/datasets were extracted to estimate trends for 10,940,801 children and adolescents from 24 high-, 4 upper-middle-, and 1 low-income countries between 1960 and 2017. Collectively, there was a negligible (per decade) improvement in SBJ performance of 1.73 cm (95% CI 1.71–1.75), 0.99% (95% CI 0.97–1.01) or a standardized effect size of 0.07 (0.07–0.07) over the entire period, with the rate of improvement steady from the 1960s to the 1980s, slowing in the 1990s, before declining. Sex- and age-related temporal differences were negligible. Trends differed between countries, with most countries experiencing declines. National trends in SBJ performance were not significantly related to national trends in health-related and socioeconomic/demographic indicators. Conclusions SBJ performance of children and adolescents has declined since 2000 (at least among most of the countries in this analysis) and is suggestive of a modern decline in functional explosive lower-body strength. Growing recognition of the importance of muscular fitness as a marker of population health highlights the need for continued tracking of temporal trends in SBJ, especially among low- and lower-middle-income countries for which temporal data are lacking. PROSPERO Registration Number CRD42013003657.

The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors. Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor. In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers. Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors. NCT00359190.

Despite the fundamental role of bacterial strain variation in gut microbiota function 1 , 2 , 3 , 4 , 5 – 6 , the number of unique strains of a species that can stably colonize the human intestine is still unknown for almost all species. Here we determine the strain richness (SR) of common gut species using thousands of sequenced bacterial isolates with paired metagenomes. We show that SR varies across species, is transferable by faecal microbiota transplantation, and is uniquely low in the gut compared with soil and lake environments. Active therapeutic administration of supraphysiologic numbers of strains per species increases recipient SR, which then converges back to the population average after dosing is ceased. Stratifying engraftment outcomes by high or low SR shows that SR predicts microbial addition or replacement in faecal transplants. Together, these results indicate that properties of the gut ecosystem govern the number of strains of each species colonizing the gut and thereby influence strain addition and replacement in faecal microbiota transplantation and defined live biotherapeutic products. Strain richness of gut microbiota ecosystems is a key characteristic underpinning engraftment in faecal microbiota transplantation, and could improve the design of defined live biotherapeutic products with predictable outcomes.

The transmembrane protein β-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer’s disease (AD). The β-amyloid hypothesis posits that aberrant processing of APP forms neurotoxic β-amyloid aggregates, which lead to the cognitive impairments observed in AD. Although numerous additional factors contribute to AD, there is a need to better understand the synaptic function of APP. We have found that Drosophila APP-like (APPL) has both shared and non-shared roles at the synapse with Kismet (Kis), a chromatin helicase binding domain (CHD) protein. Kis is the homolog of CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively. Loss of function mutations in kis and animals expressing human APP and BACE in their central nervous system show reductions in the glutamate receptor subunit, GluRIIC, the GTPase Rab11, and the bone morphogenetic protein (BMP), pMad, at the Drosophila larval neuromuscular junction (NMJ). Similarly, processes like endocytosis, larval locomotion, and neurotransmission are deficient in these animals. Our pharmacological and epistasis experiments indicate that there is a functional relationship between Kis and APPL, but Kis does not regulate appl expression at the larval NMJ. Instead, Kis likely influences the synaptic localization of APPL, possibly by promoting rab11 transcription. These data identify a potential mechanistic connection between chromatin remodeling proteins and aberrant synaptic function in AD.

Objective To estimate national and international temporal trends in handgrip strength for children and adolescents, and to examine relationships between trends in handgrip strength and trends in health-related and sociodemographic indicators. Methods Data were obtained through a systematic search of studies reporting temporal trends in the handgrip strength for apparently healthy 9–17-year-olds, and by examining large national fitness datasets. Temporal trends at the country–sex–age level were estimated by sample-weighted regression models relating the year of testing to mean handgrip strength. International and national trends were estimated by a post-stratified population-weighting procedure. Pearson’s correlations quantified relationships between national trends in handgrip strength and national trends in health-related/sociodemographic indicators. Results 2,216,320 children and adolescents from 13 high-, 5 upper-middle-, and 1 low-income countries/special administrative regions between 1967 and 2017 collectively showed a moderate improvement of 19.4% (95% CI 18.4–20.4) or 3.8% per decade (95% CI 3.6–4.0). The international rate of improvement progressively increased over time, with more recent values (post-2000) close to two times larger than those from the 1960s/1970s. Improvements were larger for children (9–12 years) compared to adolescents (13–17 years), and similar for boys and girls. Trends differed between countries, with relationships between national trends in handgrip strength and national trends in health-related/sociodemographic indicators negligible-to-weak and not statistically significant. Conclusions There has been a substantial improvement in absolute handgrip strength for children and adolescents since 1967. There is a need for improved international surveillance of handgrip strength, especially in low- and middle-income countries, to more confidently determine true international trends. PROSPERO Registration Number CRD42013003657.

Tenofovir-emtricitabine (TDF-FTC) pre-exposure prophylaxis (PrEP) has been found to be effective for prevention of HIV infection in several clinical trials. Two studies of TDF PrEP among men who have sex with men showed slight bone mineral density (BMD) loss. We investigated the effect of TDF and the interaction of TDF and hormonal contraception on BMD among HIV-uninfected African men and women. We evaluated the effects on BMD of using daily oral TDF-FTC compared to placebo among heterosexual men and women aged 18-29 years enrolled in the Botswana TDF2 PrEP study. Participants had BMD measurements at baseline and thereafter at 6-month intervals with dual-energy X-ray absorptiometry (DXA) scans at the hip, spine, and forearm. A total of 220 participants (108 TDF-FTC, 112 placebo) had baseline DXA BMD measurements at three anatomic sites. Fifteen (6.8%) participants had low baseline BMD (z-score of <-2.0 at any anatomic site), including 3/114 women (2.6%) and 12/106 men (11.3%) (p = 0.02). Low baseline BMD was associated with being underweight (p = 0.02), having high blood urea nitrogen (p = 0.02) or high alkaline phosphatase (p = 0.03), and low creatinine clearance (p = 0.04). BMD losses of >3.0% at any anatomic site at any time after baseline were significantly greater for the TDF-FTC treatment group [34/68 (50.0%) TDF-FTC vs. 26/79 (32.9%) placebo; p = 0.04]. There was a small but significant difference in the mean percent change in BMD from baseline for TDF-FTC versus placebo at all three sites at month 30 [forearm -0.84% (p = 0.01), spine -1.62% (p = 0.0002), hip -1.51% (p = 0.003)]. Use of TDF-FTC was associated with a small but statistically significant decrease in BMD at the forearm, hip and lumbar spine. A high percentage (6.8%) of healthy Batswana young adults had abnormal baseline BMD Further evaluation is needed of the longer-term use of TDF in HIV-uninfected persons. ClinicalTrials.gov NCT00448669.