Emerging concepts in dendrimer‐based nanomedicine: from design principles to clinical applications

Dendrimers are discrete nanostructures/nanoparticles with ‘onion skin‐like’ branched layers. Beginning with a core, these nanostructures grow in concentric layers to produce stepwise increases in size that are similar to the dimensions of many in vivo globular proteins. These branched tree‐like concentric layers are referred to as ‘generations’. The outer generation of each dendrimer presents a precise number of functional groups that may act as a monodispersed platform for engineering favourable nanoparticle–drug and nanoparticle–tissue interactions. These features have attracted significant attention in medicine as nanocarriers for traditional small drugs, proteins, DNA/RNA and in some instances as intrinsically active nanoscale drugs. Dendrimer‐based drugs, as well as diagnostic and imaging agents, are emerging as promising candidates for many nanomedicine applications. First, we will provide a brief survey of recent nanomedicines that are either approved or in the clinical approval process. This will be followed by an introduction to a new ‘nanoperiodic’ concept which proposes nanoparticle structure control and the engineering of ‘critical nanoscale design parameters’ (CNDPs) as a strategy for optimizing pharmocokinetics, pharmocodynamics and site‐specific targeting of disease. This paradigm has led to the emergence of CNDP‐directed nanoperiodic property patterns relating nanoparticle behaviour to critical in vivo clinical translation issues such as cellular uptake, transport, elimination, biodistribution, accumulation and nanotoxicology. With a focus on dendrimers, these CNDP‐directed nanoperiodic patterns are used as a strategy for designing and optimizing nanoparticles for a variety of drug delivery and imaging applications, including a recent dendrimer‐based theranostic nanodevice for imaging and treating cancer. Several emerging preclinical dendrimer‐based nanotherapy concepts related to inflammation, neuro‐inflammatory disorders, oncology and infectious and ocular diseases are reviewed. Finally we will consider challenges and opportunities anticipated for future clinical translation, nanotoxicology and the commercialization of nanomedicine.     

The CSD Drug Subset: The Changing Chemistry and Crystallography of Small Molecule Pharmaceuticals

We report the generation and statistical analysis of the CSD drug subset: a subset of the Cambridge Structural Database (CSD) consisting of every published small-molecule crystal structure containing an approved drug molecule. By making use of InChI matching, a CSD Python API workflow to link CSD entries to the online database Drugbank.ca has been produced. This has resulted in a subset of 8632 crystal structures, representing all published solid forms of 785 unique drug molecules. We hope that this new resource will lead to improvements in targeted cheminformatics and statistical model building in a pharmaceutical setting. In addition to this, as part of the Advanced Digital Design of Pharmaceutical Therapeutics collaboration between academia and industry, we have been given the unique opportunity to run comparative analysis on the internal crystal structure databases of AstraZeneca and Pfizer, alongside comparison to the CSD as a whole.     

From the Cover: Erosion of functional independence early in the evolution of a microbial mutualism

Many species have evolved to function as specialized mutualists, often to the detriment of their ability to survive independently. However, there are few, if any, well-controlled observations of the evolutionary processes underlying the genesis of new mutualisms. Here, we show that within the first 1,000 generations of initiating independent syntrophic interactions between a sulfate reducer (Desulfovibrio vulgaris) and a hydrogenotrophic methanogen (Methanococcus maripaludis), D. vulgaris frequently lost the capacity to grow by sulfate respiration, thus losing the primary physiological attribute of the genus. The loss of sulfate respiration was a consequence of mutations in one or more of three key genes in the pathway for sulfate respiration, required for sulfate activation (sat) and sulfate reduction to sulfite (apsA or apsB). Because loss-of-function mutations arose rapidly and independently in replicated experiments, and because these mutations were correlated with enhanced growth rate and productivity, gene loss could be attributed to natural selection, even though these mutations should significantly restrict the independence of the evolved D. vulgaris. Together, these data present an empirical demonstration that specialization for a mutualistic interaction can evolve by natural selection shortly after its origin. They also demonstrate that a sulfate-reducing bacterium can readily evolve to become a specialized syntroph, a situation that may have often occurred in nature.From flowering plants and their pollinators to the microbial endosymbionts of insects, there are many examples in nature of obligate mutualists (1, 2), or species dependent upon a mutually beneficial interaction for their survival or reproduction. How these interactions evolve is a mystery because much theory predicts that cooperative interactions should be unstable (3) and because of the difficulty of inferring evolutionary events that occurred in the distant past (4). Although there are few, if any, empirical observations of evolution toward dependence on mutualism, there are now several examples of mutualisms evolving de novo in the laboratory (5–8). This advancement has provided researchers an experimental framework to study populations and ecological conditions in the early stages of evolution (5–8).Here, we describe our observations of rapid and repeated evolution of increased dependency on a mutualism through natural selection. This interaction is similar to a widespread relationship between prokaryotes that plays a pivotal role in the decomposition of carbon in many oxygen-free environments. In these syntrophic mutualisms, bacteria ferment organic acids, producing hydrogen or formate as by-products, which are then used by hydrogen-consuming species, often methanogenic archaea (9). Removal of hydrogen and formate benefits the bacteria because the free energy (ΔG) available decreases with increasing concentrations of these products (9). A variety of bacterial species have been described that seem to be specialized for fermenting organic acids in syntrophic association with hydrogen-consuming species (10–13). Notably, most clades of characterized syntrophs share a recent common ancestry with sulfate reducers (10, 14). Some retain vestiges of the sulfate-reducing pathway, and several lines of evidence hint at the possibility that specialized syntrophs were once sulfate reducers (11, 14).Sulfate-reducing bacteria gain energy from organic acids, such as lactate, in the absence of oxygen by coupling their oxidation to the reduction of sulfate to sulfide. These bacteria play a critical role in sulfur and carbon cycling, contribute to corrosion in the petroleum industry and wastewater treatment plants, and have been used for bioremediation of toxic heavy metals (15). The ability of sulfate reducers to grow in syntrophic association with methanogens was first demonstrated in laboratory studies (16) and is now generally recognized to be of environmental relevance (17–19). Many sulfate reducers would therefore be better described as facultative syntrophs, well adapted to environments of fluctuating electron acceptor availability (17, 20). Past evolutionary transitions of sulfate-reducing bacteria between obligate and facultative syntrophs is also indicated by comparative analyses indicating horizontal transfer of genes in the pathway of sulfate respiration (21, 22). Thus, the evolutionary adaptive flexibility of sulfate-reducing bacteria suggests that they offer an attractive experimental system to study the evolution of mutualism.To understand how mutualisms, and syntrophic interactions in particular, might evolve from their origin, we paired the sulfate-reducing bacterium, Desulfovibrio vulgaris Hildenborough, with the archaeon, Methanococcus maripaludis S2, and propagated 22 initially isogenic planktonic cocultures for 1,000 generations in medium with lactate but no sulfate or added hydrogen. In this environment, neither species can gain energy from the oxidation of lactate without syntrophic cooperation.Within the first 300 generations of evolution, the cocultures evolved increased stability, higher yields, and higher growth rates, with both species contributing to these changes (6), a trend that continued through 1,000 generations. We describe a common evolutionary outcome of these experiments. Many of the independently evolved D. vulgaris accumulated loss-of-function mutations in genes required for the reduction of sulfate, suggesting strong selection for mutations resulting in loss of the ability to respire sulfate during evolution in syntrophy.     

应用正交试验减少静脉用药集中调配中心难溶性抗菌药物残留量

[摘要]目的：利用正交试验降低静脉用药调配中心难溶抗菌药物的残留量。方法：选定溶媒类型、溶媒体积和溶药针类型三个因素,每个因素确定两个水平,即溶媒类型为0.9%氯化钠注射液和灭菌注射用水,溶媒体积为5 mL和8 mL,溶药针类型为直孔溶药针和侧孔溶药针,进行三因素两水平的正交试验,考察各个因素对静脉用药调配中心难溶抗菌药物残留体积和残留量的影响。结果：影响静脉用药调配中心难溶抗菌药物残留体积的主次因素为溶药针类型最大,溶媒体积次之,溶媒类型最小;影响残留量的主次因素为溶媒体积最大,溶药针类型次之,溶媒类型最小。结论：选择适宜溶媒类型、溶媒体积和溶药针类型调配难溶性抗菌药物,可降低西林瓶内的残留量,提高成品输液质量。     

病例-病例-时间-对照设计

自身病例对照设计(如病例交叉设计、自身对照病例系列研究)虽然能控制不随时间变化的混杂因素(可测量或不可测量的)的影响,但是不能控制暴露时间变化趋势所带来的混杂.双向病例交叉设计可以控制暴露时间变化趋势.但是在药物流行病学的研究中,疾病状态通常影响后续的药物使用,因此这种双向病例交叉设计往往不适用.Suissa 提出的病例-时间-对照设计将病例交叉设计和病例对照设计相结合,很好地控制了暴露的时间变化趋势所带来的偏倚.但是当病例组和对照组不能良好地匹配时,可能会引入新的选择偏倚.本文介绍一种新的研究设计方法“病例-病例-时间-对照设计”,该研究设计是“病例-时间-对照设计”的衍生,即在选择对照组时并不采用外部对照,而是将未来病例作为当前病例的对照,从而避免了暴露的时间趋势所带来的混杂.文后还通过实例分析,对此方法的优点和局限性进行阐释.     

The Effects of Express Lane Eligibility on Medicaid and CHIP Enrollment among Children

Objective

To estimate the impact of Express Lane Eligible (ELE) implementation on Medicaid/CHIP enrollment in eight states.

Data Sources/Study Setting

2007 to 2011 data from the Statistical Enrollment Data System (SEDS) on Medicaid/CHIP enrollment.

Study Design

We estimate difference-in-difference equations, with quarter and state fixed effects. The key independent variable is an indicator for whether the state had ELE in place in the given quarter, allowing the experience of statistically matched non-ELE states to serve as a formal counterfactual against which to assess the changes in the eight ELE states. The model also controls for time-varying economic and policy factors within each state.

Data Collection/Extraction Methods

We obtained SEDS enrollment data from CMS.

Principal Findings

Across model specifications, the ELE effects on Medicaid enrollment among children were consistently positive, ranging between 4.0 and 7.3 percent, with most estimates statistically significant at the 5 percent level. We also find that ELE increased combined Medicaid/CHIP enrollment.

Conclusions

Our results imply that ELE has been an effective way for states to increase enrollment and retention among children eligible for Medicaid/CHIP. These results also imply that ELE-like policies could improve take-up of subsidized coverage under the ACA.     

Placebo use in vaccine trials: Recommendations of a WHO expert panel

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.