The influence of pregnancy on the pharmacokinetic properties of artemisinin combination therapy (ACT): a systematic review

Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs, including the different components of artemisinin-based combination therapy (ACT). However, small sample sizes make it difficult to draw strong conclusions based on individual pharmacokinetic studies. The aim of this review is to summarize the evidence of the influence of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations. A PROSPERO-registered systematic review to identify clinical trials that investigated the influence of pregnancy on the pharmacokinetic properties of different forms of ACT was conducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, Biosis Previews and the African Index Medicus were searched for studies published up to November 2015. The following components of ACT that are currently recommend by the World Health Organization as first-line treatment of malaria in pregnancy were reviewed: artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil. The literature search identified 121 reports, 27 original studies were included. 829 pregnant women were included in the analysis. Comparison of the available studies showed lower maximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the active metabolite of all artemisinin derivatives, after oral administration of artemether, artesunate and dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seen in lumefantrine studies, indicating a low exposure and possibly reduced efficacy. The influence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant. Sulfadoxine plasma concentration was significantly reduced and clearance rates were higher in pregnancy, while pyrimethamine and mefloquine need more research as no general conclusion can be drawn based on the available evidence. For atovaquone, the available data showed a lower maximum concentration and exposure. Finally, the maximum concentration of cycloguanil, the active metabolite of proguanil, was significantly lower, possibly compromising the efficacy. These findings suggest that reassessment of the dose of the artemisinin derivate and some components of ACT are necessary to ensure the highest possible efficacy of malaria treatment in pregnant women. However, for most components of ACT, data were insufficient and extensive research with larger sample sizes will be necessary to identify the exact influences of pregnancy on the pharmacokinetic properties of different artemisinin-based combinations. In addition, different clinical studies used diverse study designs with various reported relevant outcomes. Future pharmacokinetic studies could benefit from more uniform designs, in order to increase quality, robustness and effectiveness. CRD42015023756 (PROSPERO

Understanding urbanicity: how interdisciplinary methods help to unravel the effects of the city on mental health

Twenty-first century urbanization poses increasing challenges for mental health. Epidemiological studies have shown that mental health problems often accumulate in urban areas, compared to rural areas, and suggested possible underlying causes associated with the social and physical urban environments. Emerging work indicates complex urban effects that depend on many individual and contextual factors at neighbourhood and country level and novel experimental work is starting to dissect potential underlying mechanisms. This review summarizes findings from epidemiology and population- based studies, neuroscience, experimental, and experience-based research and illustrates how a combined approach can move the field towards an increased understanding of the urbanicity-mental health nexus

Mid-term clinical results of chronic cavitary long bone osteomyelitis treatment using S53P4 bioactive glass:A multi-center study

Introduction: Chronic osteomyelitis is a challenging condition in the orthopedic practice and traditionally treated using local and systemic antibiotics in a two-stage surgical procedure. With the introduction of the antimicrobial biomaterial S53P4 bioactive glass (Bonalive®), chronic osteomyelitis can be treated in a one-stage procedure. This study evaluated the mid-term clinical results of patients treated with S53P4 bioactive glass for long bone chronic osteomyelitis. Methods: In this prospective multi-center study, patients from two different university medical centers in the Netherlands were included. One-stage treatment consisted of debridement surgery, implantation of S53P4 bioactive glass, and treatment with culture-based systemic antibiotics. If required, wound closure by a plastic surgeon was performed. The primary outcome was the eradication of infection, and a secondary statistical analysis was performed on probable risk factors for treatment failure. Results: In total, 78 patients with chronic cavitary long bone osteomyelitis were included. Follow-up was at least 12 months (mean 46; standard deviation, SD, 20), and 69 patients were treated in a one-stage procedure. Overall infection eradication was 85 %, and 1-year infection-free survival was 89 %. Primary closure versus local/muscular flap coverage is the only risk factor for treatment failure. Conclusion: With 85 % eradication of infection, S53P4 bioactive glass is an effective biomaterial in the treatment of chronic osteomyelitis in a one-stage procedure. A major risk factor for treatment failure is the necessity for local/free muscle flap coverage. These results confirm earlier published data, and together with the fundamentally different antimicrobial pathways without antibiotic resistance, S53P4 bioactive glass is a recommendable biomaterial for chronic osteomyelitis treatment and might be beneficial over other biomaterials.</p

Sex Differences in Cooperation: A Meta-analytic Review of Social Dilemmas

Although it is commonly believed that women are kinder and more cooperative than men, there is conflicting evidence for this assertion. Current theories of sex differences in social behavior suggest that it may be useful to examine in what situations men and women are likely to differ in cooperation. Here, we derive predictions from both sociocultural and evolutionary perspectives on context-specific sex differences in cooperation, and we conduct a unique meta-analytic study of 272 effect sizes—sampled across 50 years of research—on social dilemmas to examine several potential moderators. The overall average effect size is not statistically different from zero (d –0.05), suggesting that men and women do not differ in their overall amounts of cooperation. However, the association between sex and cooperation is moderated by several key features of the social context: Male–male interactions are more cooperative than female–female interactions (d 0.16), yet women cooperate more than men in mixed-sex interactions (d –0.22). In repeated interactions, men are more cooperative than women. Women were more cooperative than men in larger groups and in more recent studies, but these differences disappeared after statistically controlling for several study characteristics. We discuss these results in the context of both sociocultural and evolutionary theories of sex differences, stress the nee

Dynamics of Parasite Clearance in Cutaneous Leishmaniasis Patients Treated with Miltefosine

Parasite loads were quantified in repeated skin biopsies from lesions of 2 patients with Old-World cutaneous leishmaniasis (CL) caused by Leishmania major and L. infantum during and after treatment with miltefosine. Miltefosine induced a rapid therapeutic effect on both infections with an initial decline of parasites of ∼1 log/week for the L. major infection. These observations illustrate the usability of quantifying parasite loads in skin lesions as a pharmacodynamic measure and quantitative descriptor of drug effect for CL supporting clinical assessment

Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity

Triple-negative breast cancers (TNBCs) display great diversity in cisplatin sensitivity that cannot be explained solely by cancer-associated DNA repair defects. Differential activation of the DNA damage response (DDR) to cisplatin has been proposed to underlie the observed differential sensitivity, but it has not been investigated systematically. Systems-level analysis-using quantitative time-resolved signaling data and phenotypic responses, in combination with mathematical modeling-identifies that the activation status of cell-cycle checkpoints determines cisplatin sensitivity in TNBC cell lines. Specifically, inactivation of the cell-cycle checkpoint regulator MK2 or G3BP2 sensitizes cisplatin-resistant TNBC cell lines to cisplatin. Dynamic signaling data of five cell cycle-related signals predicts cisplatin sensitivity of TNBC cell lines. We provide a time-resolved map of cisplatin-induced signaling that uncovers determinants of chemo-sensitivity, underscores the impact of cell-cycle checkpoints on cisplatin sensitivity, and offers starting points to optimize treatment efficacy