Given the enormous burden placed on regulatory agencies to assess and manage an ever growing list of nanomaterials of various classes and properties, optimization and validation of alternative toxicity testing strategies including in vitro, ex vivo, and in silico methods, that aim to reduce or refine the involvement of animal testing methods, has become mandatory. However, in a regulatory context, to be effective, an alternative approach is expected to include a suite of tests that target different components of the underlying toxicity mechanism using different endpoints and assays. In the absence of in depth understanding of the involved biology and the biology being assessed by the alternatives, this exercise can rapidly reach a chaotic proportion and the initial objectives of rapid or timely and effective toxicity assessment can be easily lost. This review presents an overview of the AOP framework and its importance as support tool for effective development of alternative toxicity testing strategies for nanomaterials. Various AOPs of relevance to inhalation toxicity of nanomaterials that are currently under various stages of development are summarized and an AOP-informed tiered alternative testing strategy is proposed for the assessment of lung fibrosis. The review builds a solid case to 1) demonstrate how inclusion of AOP thinking that allows the design of mechanism-informed assays targeting most critical events in the path of a disease helps progress assessment of nanomaterials for their potential to induce human health impacts and 2) demonstrate how combination of high-content data (omics) to inform the development of an AOP and the design of AOP-informed assays targeting multiple key events, will expedite the progress in this field. Lastly, a few of the important issues that have plagued the development of AOPs in general and continue to impact their development as relevant to nanotoxicity are discussed.
In clinical research, RCT is not always feasible ; therefore, non-randomized design remains considerable. In non-randomised study (also called quasi-experimental studies), investigators control the allocation of participants into groups, but do not attempt to adopt randomized operation , including follow-up study. According to with or without comparison, non-randomized clinical intervention study can be divided into comparative and non-comparative sub-types, the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool  is the preferentially recommended tool. This tool is developed to evaluate risk of bias in estimating comparative effectiveness (harm or benefit) of interventions in studies not adopting randomization in allocating units (individuals or clusters of individuals) into comparison groups. Besides, the JBI critical appraisal checklist for quasi-experimental studies (non-randomized experimental studies) is also suitable, which includes 9 items. Moreover, the methodological index for non-randomized studies (MINORS)  tool can also be used, which contains a total of 12 methodological points; the first 8 items could be applied for both non-comparative and comparative studies, while the last 4 items appropriate for studies with two or more groups. Every item is scored from 0 to 2, and the total scores over 16 or 24 give an overall quality score. Table S1K-L-M presented the major items of these three tools.
For assessing the quality of analytical cross-sectional study, the NIH quality assessment tool for observational cohort and cross-sectional studies (Table S2C), JBI critical appraisal checklist for analytical cross-sectional study (Table S2K), and the Appraisal tool for Cross-Sectional Studies (AXIS tool; Table S2L)  are recommended tools. The AXIS tool is a critical appraisal tool that addresses study design and reporting quality as well as the risk of bias in cross-sectional study, which was developed in 2016 and contains 20 items. Among these three tools, the JBI checklist is the most preferred one.
Clinical prediction study includes predictor finding (prognostic factor) studies, prediction model studies (development, validation, and extending or updating), and prediction model impact studies . For predictor finding study, the Quality In Prognosis Studies (QIPS) tool  can be used for assessing its methodological quality (Table S3H). For prediction model impact studies, if it uses a randomized comparative design, tools for RCT can be used, especially the RoB 2.0 tool; if it uses a nonrandomized comparative design, tools for non-randomized studies can be used, especially the ROBINS-I tool. For diagnostic and prognostic prediction model studies, the Prediction model Risk Of Bias Assessment Tool (PROBAST; Table S3I)  and CASP clinical prediction rule checklist (Table S3J) are suitable.
In the humanitarian sector, for example, speculative design has been used to help organizations consider the future of their work in a rapidly changing world. HUM.2035 is a project that developed forecasts for how humanitarian work would fundamentally change based on the shifting nature and location of crises caused by climate change, livelihoods disruption, geopolitics, digitalization, et al. The process used tools and techniques from the field of speculative design.
When you set up the meetings tool, you connect your calendar to HubSpot. When a prospect is on your meetings page, they'll see all open slots on your calendar that are marked as free. If you have events on your calendar that are set to busy, they will not show as a bookable time.
Hi,Is there a way to allow for people to download my freebie as many times as they wish?It looks like subscribers can only receive my Ebook when they submit their emails for the first time.Thanks,
Its me again. Upon further digging, the free version of mailchimp appears to allow for a welcome email to be sent to new list signups. This could be a workaround and I hope to be able to use this to include a link to a hidden page on my website where email subscribers can download my freebie there. Thanks again!
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I rummaged through all the comments to see if there was a way to avoid putting re-subscribers through the hassle of updating preferences, which I have found confuses them. and would like to share my solution after many hours of brain-bulging!. This applies to a specific campaign when a free book download is offered to all subscribers and is also shared on social media in the hope of gaining new subscribers. I targeted the email campaign to my main list, linked this to a landing page with the sign-up form. The sign-up form triggered an automatic welcome email, as you suggested, but this must be linked to a NEW list created for this specific purpose and must have the download file in it. In this way, everyone receives their book easily. Later, when the campaign is over, it is easy to send the contacts on the NEW list to your main list, and any duplicates are automatically updated. I hope this helps.
Hi,Thanks so much for this article. I had been searching online for a straight forward explanation for this and was so confused until I found this site. Just two questions. So after following this steps is it correct to say that right now new subscribers (whether it is through this opt in or my Facebook sign up button or my newsletter sign up button on the sidebar) will be able to download my free printable?
Hello,When I add my PDF to MailChimp, it shows up in the confirm subscription email and the confirmation page. How do I keep it from showing up in the confirm subscription page? If it continues to show up, my readers will be able to get my free download without having to actually sign up. ?
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Although it might seem a little old (the original copyright dates back to 1943), this book presents relevant and fundamental methods, techniques, and practices for designing and manufacturing tools, gages, dies, and fixtures. 2b1af7f3a8