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KA Group

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Fx Tools Johnson Controls.epub

Interpretation: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer.

Fx Tools Johnson Controls.epub

To date, a total of 22 double-blind controlled clinical trials in FXS have been identified through and an extensive literature search. The vast majority of these FDA/NIH-registered clinical trials has been completed between 2008 and 2015 and has targeted the core excitatory/inhibitory imbalance present in FXS and other neurodevelopmental disorders. Limited data exist on reliability and validity for most tools used to measure cognitive, behavioral, and other problems in FXS in these trials and other studies. Overall, evidence for most tools supports a moderate tool quality grading. Data on sensitivity to treatment, currently under evaluation, could improve ratings for some cognitive and behavioral tools. Some progress has also been made at identifying promising biomarkers, mainly on blood-based and neurophysiological measures.

Despite the tangible progress in implementing clinical trials in FXS, the increasing data on measurement properties of endpoints, and the ongoing process of new tool development, the vast majority of outcome measures are at the moderate quality level with limited information on reliability, validity, and sensitivity to treatment. This situation is not unique to FXS, since reviews of endpoints for ASD have arrived at similar conclusions. These findings, in conjunction with the predominance of parent-based measures particularly in the behavioral domain, indicate that endpoint development in FXS needs to continue with an emphasis on more objective measures (observational, direct testing, biomarkers) that reflect meaningful improvements in quality of life. A major continuous challenge is the development of measurement tools concurrently with testing drug safety and efficacy in clinical trials.

Most of the conclusions of the Working Groups continue to be valid. As the 2013 Report indicated, there is only sparse evidence on reliability and validity for most of the instruments used to measure cognitive deficits in FXS. However, several pilot projects with high potential cognitive measures (KiTAP, ELS, NIH-TCB) have been completed since the 2013 Report and larger validation studies are in preparation or ongoing. Thus, new data in the Cognition domain may lead to stronger recommendations for some tools in the next few years. In terms of adaptive behavior, an area with a long track record of observational studies in FXS, new measures including the ILS, and the W-ADL, are promising but need to be formally assessed. It is expected that the recently released Vineland-3 will perform similarly to the Vineland-II in FXS, although will be more relevant to current adaptive skills (e.g., electronic device use). Studies to evaluate the Vineland-3 in FXS are underway. We conclude that the overall evidence for cognition-related outcome measures in FXS places them in the limited to moderate quality range, with most instruments adequate for assessment of longer-term changes (i.e., some evaluating specific cognitive functions may be appropriate as shorter-term endpoints).

Evidence for the PARS and ADAMS reviewed here support their promising status as moderate quality tools, in part because of the lack of information on sensitivity to change. As indicated above, these instruments could be used for measuring either shorter- or longer-term outcomes. Until these tools are fully evaluated and shown to detect change in intervention studies, it will not be clear if they are adequate as primary endpoints for the assessment of anxiety in FXS. A few other measures, such as the RCADS and the SCARED, could be potentially useful in higher functioning individuals with FXS (i.e., most females). Nevertheless, considering that anxiety is a major behavioral abnormality in FXS, development of anxiety measures with better psychometric properties is still a worthwhile goal.

Overall, the authors concluded that only sparse evidence exists on reliability and validity for only a few of the tools used in young children with ASD, probably the group of greater relevance to FXS. Since our literature search revealed that only in idiopathic ASD there has been a systematic review of the tools in terms of measurement properties, we focus on those instruments without having separate sections for ASD in FXS and idiopathic ASD.

These are promising tools; however, the body of evidence supporting their use as outcome measures is still small. Despite this, the unique properties of biomarkers (e.g., objectivity, direct demonstration of target engagement) suggest that their inclusion in future studies developing endpoints or in early-phase intervention studies is critical.

We have focused primarily on global brain phenotypes, which were measurable in the largest achievable sample, aggregated over the widest age range, with the fewest methodological, theoretical and data-sharing constraints. However, we have also provided proof-of-concept brain charts for regional grey matter volumetrics, demonstrating plausible heterochronicity of cortical patterning, and illustrating the potential generalizability of this approach to a diverse range of fine-grained MRI phenotypes (Fig. 2, Supplementary Information 8). As ongoing and future efforts provide increasing amounts of high-quality MRI data, we predict an iterative process of improved brain charts for an increasing number of multimodal72 neuroimaging phenotypes. Such diversification will require the development, implementation and standardization of additional data quality control procedures27 to underpin robust brain chart modelling. To facilitate further research using our reference charts, we have provided interactive tools to explore these statistical models and to derive normalized centile scores for new datasets across the lifespan at

Gene inactivation through RNA interference (RNAi) has proven to be a valuable tool for studying gene function in C. elegans. When combined with tissue-specific gene inactivation methods, RNAi has the potential to shed light on the function of a gene in distinct tissues. In this study we characterized C. elegans rrf-1 mutants to determine their ability to process RNAi in various tissues. These mutants have been widely used in RNAi studies to assess the function of genes specifically in the C. elegans germline. Upon closer analysis, we found that two rrf-1 mutants carrying different loss-of-function alleles were capable of processing RNAi targeting several somatically expressed genes. Specifically, we observed that the intestine was able to process RNAi triggers efficiently, whereas cells in the hypodermis showed partial susceptibility to RNAi in rrf-1 mutants. Other somatic tissues in rrf-1 mutants, such as the muscles and the somatic gonad, appeared resistant to RNAi. In addition to these observations, we found that the rrf-1(pk1417) mutation induced the expression of several transgenic arrays, including the FOXO transcription factor DAF-16. Unexpectedly, rrf-1(pk1417) mutants showed increased endogenous expression of the DAF-16 target gene sod-3; however, the lifespan and thermo-tolerance of rrf-1(pk1417) mutants were similar to those of wild-type animals. In sum, these data show that rrf-1 mutants display several phenotypes not previously appreciated, including broader tissue-specific RNAi-processing capabilities, and our results underscore the need for careful characterization of tissue-specific RNAi tools.

Key advantages of using C. elegans as a model organism for genetic studies is its experimental tractability while displaying physiological complexity with multiple specialized tissues. The study of tissue-specific functions of genes using RNAi techniques requires robust tissue-selective tools. To address whether the rrf-1 mutant is an efficient tool for probing the function of genes specifically in the germline, we have characterized the effect of rrf-1 mutations on processing RNAi in various specialized tissues in C. elegans. We confirmed that rrf-1 mutants are able to process RNAi efficiently in the germline, and are resistant to RNAi in the muscle, as reported previously [7]. However, we found that rrf-1 mutants are capable of processing RNAi in the intestinal soma against several endogenous genes as well as GFP reporters expressed in the intestine. We also used transgenic reporters to assess the RNAi-processing capabilities of other somatic tissues in rrf-1 mutants, and found that transgene reduction occurred in a subset of hypodermal cells, the seam cells, whereas the somatic gonad was resistant to gfp RNAi. In contrast, the hypodermis was resistant to RNAi against at least two endogenous targets, suggesting that this somatic tissue may be able to process RNAi in some, but not all, cells. Taken together, these results show that the rrf-1 mutants are sensitive to at least some RNAi triggers in somatic tissues, most notably in the intestine. In addition to imparting an ability to process somatic RNAi, we found that the rrf-1(pk1417) mutation also increased the expression of some transgenes in somatic tissues. Lastly, we discovered that the rrf-1 mutant displayed increased endogenous expression of the FOXO transcription factor DAF-16 target gene sod-3, a superoxide dismutase, suggesting that rrf-1 mutants may have increased DAF-16 activity. While DAF-16 is a key modulator of C. elegans longevity, the possible increase in its activity in rrf-1 mutants does not translate into an extended lifespan or increased stress resistance. Our characterization of the rrf-1 mutant highlights the need for researchers to exercise caution in using this mutant as a tissue-specific RNAi tool, including in the study of longevity pathways with relevance to the FOXO transcription factor DAF-16.


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