Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria

Background The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. Patients and methods Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. Results A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h). Conclusions This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/

Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index

Background Cigarette smoking is associated with lower body mass index (BMI), and a commonly cited reason for unwillingness to quit smoking is a concern about weight gain. Common variation in the CHRNA5-CHRNA3-CHRNB4 gene region (chromosome 15q25) is robustly associated with smoking quantity in smokers, but its association with BMI is unknown. We hypothesized that genotype would accurately reflect smoking exposure and that, if smoking were causally related to weight, it would be associated with BMI in smokers, but not in never smokers. Methods We stratified nine European study samples by smoking status and, in each stratum, analysed the association between genotype of the 15q25 SNP, rs1051730, and BMI. We meta-analysed the results (n = 24 198) and then tested for a genotype × smoking status interaction. Results There was no evidence of association between BMI and genotype in the never smokers {difference per T-allele: 0.05 kg/m2 [95% confidence interval (95% CI): −0.05 to 0.18]; P = 0.25}. However, in ever smokers, each additional smoking-related T-allele was associated with a 0.23 kg/m2 (95% CI: 0.13-0.31) lower BMI (P = 8 × 10−6). The effect size was larger in current [0.33 kg/m2 lower BMI per T-allele (95% CI: 0.18-0.48); P = 6 × 10−5], than in former smokers [0.16 kg/m2 (95% CI: 0.03-0.29); P = 0.01]. There was strong evidence of genotype × smoking interaction (P = 0.0001). Conclusions Smoking status modifies the association between the 15q25 variant and BMI, which strengthens evidence that smoking exposure is causally associated with reduced BMI. Smoking cessation initiatives might be more successful if they include support to maintain a healthy BM

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Somatic retrotransposition alters the genetic landscape of the human brain

Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes

Environmentalism, pre-environmentalism, and public policy

In the last decade, thousands of new grassroots groups have formed to oppose environmental pollution on the basis that it endangers their health. These groups have revitalized the environmental movement and enlarged its membership well beyond the middle class. Scientists, however, have been unable to corroborate these groups' claims that exposure to pollutants has caused their diseases. For policy analysts this situation appears to pose a choice between democracy and science. It needn't. Instead of evaluating the grassroots groups from the perspective of science, it is possible to evaluate science from the perspective of environmentalism. This paper argues that environmental epidemiology reflects ‘pre-environmentalist’ assumptions about nature and that new ideas about nature advanced by the environmental movement could change the way scientists collect and interpret data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45449/1/11077_2005_Article_BF01006494.pd

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century