Future perspectives. The methodological issues identified through simulation scenarios and the lessons learned from the integrated experimental protocol developed for naproxen have highlighted the limitations of current practice in the evaluation of the safety profile of new chemical entities. More specifically, our findings reveal that inferences about safe exposure as well as the risk associated with long term use of a compound cannot be achieved by scattered empirical experimentation. A framework is required that enables integration, in a parametric manner, of experimental data and theoretical knowledge. As shown in figure 1, such a framework would encompass multidimensional data, allowing for the incorporation of not only in vivo, but also in vitro data as input for computational models. -
Future perspectives. Even though this review cannot conclude effectiveness of AT for anxiety in adults, that does not mean that AT does not work. Art therapists and other care professionals do experience the high potential of AT in clinical practice. It is challenging to find ways to objectify these practical experiences. The results of the systematic review demonstrate that high quality trials studying effectiveness and working mechanisms of AT for anxiety disorders in general and specifically, and for people with anxiety in specific situations are still lacking. To get high quality evidence of effectiveness of AT on anxiety (disorders), more robust studies are needed. Besides anxiety symptoms, the effectiveness of AT on aspects of self-regulation like emotion regulation, cognitive regulation and stress regulation should be further studied as well. By evaluating the changes that may occur in the different areas of self-regulation, better hypotheses can be generated with respect to the working mechanisms of AT in the treatment of anxiety. A key point for AT researchers in developing, executing and reporting on RCTs, is the issue of risk of bias. It is recommended to address more specifically how RoB was minimalized in the design and execution of the study. This can lower the RoB and therefor enhance the quality of the evidence, as judged by reviewers. One of the scientific challenges here is how to assess performance bias in AT reviews. Since blinding of therapists and patients in AT is impossible, and if performance bias is only considered by ‘lack of blinding of patients and personnel’, every trial on art therapy will have a high risk on performance bias, making the overall RoB high. This implies that high or even medium quality of evidence can never be reached for this intervention, even when all other aspects of the study are of high quality. Behavioural interventions, like psychotherapy and other complex interventions, face the same challenge. In 2017, Xxxxxx & Xxxxx (2017) published considerations on how to use the Cochrane's risk of bias tool in psychotherapy outcome research. We fully support the recommendations of Xxxxx and colleagues (2016) and would like to emphasize that tools for assessing risk of bias and quality of evidence need to be tailored to art therapy and (other) complex interventions where blinding is not possible.
Future perspectives. The process as facilitated in Wau, Gogrial and Tonj states can be tested in other areas, but it will likely not unfold in the same fashion, because blueprints are not possible. But the results may be equally valuable, if all relevant stakeholders are willing to make an effort. The commitment of the communities, including their leaders and government, is key. The Local Government Board of the Government of South Sudan and the South Sudan Peace and Reconciliation Commission (SSPRC) have endorsed the process. After two years of successful implementation by the communities and a growing interest in the region to accede to the Xxxxxx Xxx Agreement and the Interstate Policy, they see substantial potential in its replication in other parts of the country. About the organisation VNG International was established in 1993 by the Association of Netherlands Municipalities (VNG). The organisation is located in VNG’s headquarters and has easy access to all VNG’s know-how, experience and facilities. More than 50 highly motivated professionals work for VNG International in The Hague and a further 100 in project offices worldwide. We mobilise local government expertise through our global network of professionals, including a core group of some 30 associated experts who work for us on a long-term or regular basis. R
Future perspectives. Finding a conditioning regimen that is efficacious, but has minimal side effects is very challenging. Significant improvements have been made to optimize conditioning regimens by using less toxic agents, less toxic combinations and dose optimization. Xxxxxxxxxx has been introduced as a less toxic alternative for busulfan, now a little over 10-15 years ago. Still, knowledge about the pharmacokinetics and dynamics of treosulfan in the pediatric HSCT setting is limited, as are results on long term clinical outcome. This thesis has provided important new insights in the pharmacokinetics and dynamics of treosulfan, but are we there yet? There are still some questions that remain unanswered and can be addressed in future research. Our research mainly focused on nonmalignant pediatric patients. Treosulfan is also used as a conditioning agent for malignant diseases and the relationship between treosulfan exposure and clinical outcome parameters, such as relapse, have not been investigated in the pediatric setting. It is not known if the currently available data can also be applied to malignant diseases, such as acute lymphoblastic leukemia (ALL). Recently, the first results of the For Omitting Radiation Under Majority age (FORUM) study have been published; a prospective, randomized, controlled trial in which busulfan- and treosulfan-based conditioning regimens are directly compared to a traditional total body irradiation (TBI)-based regimen in pediatric patients with ALL [17]. The randomization study was prematurely stopped when the relapse incidence in both chemotherapy arms was found to be significantly higher compared to the TBI-based arm. No difference in relapse rate was found between the busulfan- and treosulfan-based arms. However, a difference between the two chemo-based arms in the FORUM study is that a significant proportion of patients in the busulfan arm had PK analysis performed, with subsequent TDM. For treosulfan, TDM-adjusted dosing was not performed. We have conducted an add-on study in the FORUM trial focused on the PK of treosulfan and its relationship with clinical outcome. The data of this add-on study are currently being collected and the final analysis has to be awaited, but so far preliminary data do not point to a clear correlation between exposure and relapse [18]. Furthermore, identifying specific patient groups that could benefit from TDM of treosulfan should ideally be performed. Such a study requires large number of patients and can b...
Future perspectives. The current evidence shows that findings from randomised studies on the treatment of rectal cancer cannot be automatically applied to elderly patients, in whom treatment of rectal cancer is a multidimensional issue. Apart from being an oncological problem, this issue is also associated with the physiological changes caused by aging, whereby patients become more vulnerable to noxious effects, which are often exaggerated by comorbid conditions. Population-based studies often claim that elderly patients, who undergo the same cancer treatment as their younger counterparts, have a more favour- able outcome than elderly patients who do not have these treatments,22 and under- treatment of the elderly has been suggested as the reason for decreased rectal-cancer- specific survival in this population.23 However, these studies do not provide convincing evidence that elderly patients should have the same treatment as younger patients. The factors responsible for the obvious selection bias when recruiting elderly patients into clinical trials are not well explained. Sufficient evidence exists to support the statement that cancer-specific survival after major resection is not age dependent.24-29 However, all researchers agree that postoperative mortality is at least doubled in elderly patients after resection compared with younger patients after resection and that careful selec- tion should be made. None of the studies provided data for 6-month mortality, but, as can be noted from our analysis presented in Table 1, a further doubling of postoperative mortality at 6 months and thereafter is very likely. Thus, major surgical treatment might not be the best option for all elderly patients with rectal cancer. However, biological age is not the only factor to be taken into account when including patients in this at-risk group, and more reliable parameters are mandatory when selecting patients for certain treatments. Obviously, in the very fit (i.e., American Society of Anesthesiologists (ASA) grade I) and the very ill (XXX XX-V) the decision to treat with curative intent or to provide palliative care is not difficult to make. The Association of Coloproctology of Great Britain and Ireland (ACPGBI) has developed an excellent scoring system for 30-day mortality on the basis of a prospective survey of more than 8077 pa- tients with colorectal cancer in 79 hospitals (ACPGBI Colorectal Cancer Study).30,31 Several other scoring systems (i.e., Possum, P-Possum, and CR-Possum) have a...
Future perspectives biomass gasification with CCS - biomass to hydrogen - biochar applied in steel industry for carbon reduction - polygeneration of hydrogen and carbon based fertilizer - gasification of landfill excavation waste Production of SNG and biomethane strategy as well as scenarios for 2030 and 2050 were presented. Gasification and SNG valorization – overview of some gasification plants - industrialization is planned with project “Salamandre” (biomethane 20 MW) - gasification 15 MWth - commercialization ongoing India energy share was presented; coal is dominating in energy mix. Bioenergy share in total energy consumption is about 26%. Ambitious target of 500 GW RES capacity by 2030. The current availability of biomass in India is estimated at about ~750 million metric tons per year with surplus availability of at about 230 million metric tons per annum equivalent to potential of about 28 GW. Bioenergy deployment Biomass co-firing in coal based power plants in India is an actual topic. It was decided to co-fire 5- 10% of biomass in all thermal power plants. • Sep up based on Praj’s proprietary technology processing Rice Straw as feedstock for the production of Ethanol • Can process 2 lakh tonnes of rice straw annually to generate around 3 crore litres of Ethanol • Assist to meet India’s target of 20% ethanol blending in petrol by 2025 • Honorable prime minister launched NHM on India's 75th Independence Day Aims to make India a green hydrogen hub as well as export of green hydrogen Green H2 spearhead India’s transition to clean energy and aid in meeting India’s climate targets India’s total hydrogen demand expected to be nearly double from current 6.7 Mt to 11.7 Mt by 2030 Govt. has plans to bring down cost of green hydrogen to Rs 160 per kg by 2029-30 Aims to extend PLI scheme for manufacturing electrolyzers Ministry of Power notified Green Hydrogen/ Green Ammonia Policy on 17th Feb, 2022 • Hydrogen/ ammonia produced from biomass named as GREEN • Waiver of inter-state transmission charges for 25 years to producers of green hydrogen from the plants commissioned before 30th June, 2025 • Open access to be granted for sourcing renewable energy within 15 days of receipt of application • The world’s largest electrolysis capacity of over 60 GW/ 5 million tonnes by 2030 for domestic consumption • The world’s largest production of green steel at 15-20 million tonnes by 2030 • The world’s largest electrolyser annual manufacturing capacity of 25 GW by 2028 delivering affordable...
Future perspectives. The overarching goal of this thesis was to find starting points to improve the prescribing of antimicrobials to slow down the unavoidable increasing prevalence of AMR. The results from this thesis showed that antimicrobial prescribing in Dutch primary care can generally be considered as prudent. Dutch GPs tend to follow the recommendations provided by the guidelines (chapter 6), resulting in a lower prescription rate in primary care when compared to many other European countries (65). However, there is still room for improvement as can be deducted from the results of the studies described in chapter 5 and 6. Here we found that there is an overprescribing of antimicrobial therapy for RTIs and that there is an overuse of macrolides. In addition, the incorrect registrations of antibiotic allergies lead to avoidable prescription of broad-spectrum instead of low-spectrum antimicrobials. It is clear that these elements need to be improved. An extra challenge in primary care regarding AMR is formed by epidemiological changes in the Dutch population, such as aging and the therewith increasing number of co-morbidities. Both are associated with antimicrobial overprescribing (chapter 3 and 6) and will probably lead to more antimicrobial use in the long-term with the risk of an increasing AMR prevalence. This makes the previously described need for improvement and continuation of already prudent antimicrobial prescribing practices even more important. The aging population and increasing number of comorbidities will increase patients need to consult a GP for RTI symptoms as they seek reassurance (10-12). This need can not only be addressed through consultation in a primary care practice, as GPS are already experiencing to be overloaded with work. To address this need, other ways of communicating with and informing of patients has to be researched and implemented. For example, mass media campaigns informing patients on the self-limiting character of RTIs and interactive websites or smartphone apps informing patients when they have contact the primary care. Another aspect regarding interventions, they have to focus on patient groups who visit a primary care practice more often and use more antimicrobials, as current interventions are mostly ‘one size fits all’. There is a need for tailored made interventions as shown in this thesis. For example, compared with other migrants groups, patients with a Turkish, Surinamese and Dutch-Caribbean background were more often prescri...
Future perspectives. In this subsection, we discuss about the future of ML for time-to-event data. While throughout the years a substantial increase in ML articles in medical research can be observed, there are few algorithms actually implemented in clinical practice [37, 66]. Below, we report some major challenges which need to be addressed prior to the establishment of ML methods. • Access to medical data. Clinical data are (rightfully) challenging to access. An informed consent and ethics committee approval, as well as appropriate handling (anonymisation) are required before data sharing [67]. Limited public data availability also hinders the validation of ML algorithms and their results by other authors. Findings obtained with a set of methodologies are not easily comparable with different datasets (as they reflect other real-life settings). • Model complexity in relation to the amount of available data. Clinical data typically include tens to thousands of patients. This number is usually not sufficiently large for the employment of modern flexible ML techniques such as neural networks which are data hungry [63, 68]. Hence, there is a substantial risk of overfitting (excessive tailoring of algorithms on training data), thus limiting the ability of these models to generalise (accurately perform) on new data. The use of shallower neural networks (one hidden layer) could reduce the risk of overfitting. ML techniques should preferably be employed for large datasets. • Clinical validation. It is the most critical component of performance assessment. The presence of missing data, regional variations in practice, and logistical/infrastructural limitations may complicate model vali- dation [69]. If possible, an external validation (e.g., using population from different centers) should follow a meticulous internal validation. Transparent reporting of ML prediction models is required [40, 44]. Both aspects of model discrimination and calibration should be taken into account for performance evaluation [41, 70]. Advantages and shortcomings in comparison with traditional benchmarks (SM) should be doc- umented. Recently, researchers are increasingly aware of the scientific rigor needed to be demonstrated prior to the employment of a ML model in clinical practice. • Model interpretation. This is a key obstacle for the integration of ML methods in medicine. For example, (deep) neural networks are called ”black boxes” since they develop complex internal functions that are hard to interpret...
Future perspectives. In this subsection, we provide some recommendations for future research in STS. STS subtypes are very heterogeneous rare malignancies with widely varying presentation, sensitivity to treatment, and long-term outcomes [7, 31]. The work provided in Chapter 2 and Chapter 3 will help to optimise the de- sign of new histology-tailored phase II trials for common histotypes (: leiomyosarcoma, liposarcoma, synovial sarcoma) in advanced or metastatic setting. Further meta-analyses should be designed and performed by using summary estimates or individual patient data for other frequent types such as undifferentiated pleomorphic sar- coma or angiosarcoma. Efficient data sharing could be key to simplify this process, as well as an international collaboration between data centers. We would like to stress the importance of designing robust and efficient phase II studies especially in rare cancers, where there is lack of evidence to support clinical decisions. Our projects have yielded a good historical control database with updated reference values which can be used to design new single arm STS studies (with a sufficient sample size and within a reasonable time-frame). This will lead to a better early evaluation of drug activity as an urgent need remains for the development of personalised treatment plans such as immunotherapy to move away from the conventional chemotherapy options. Randomised controlled trials are considered to be the gold standard for clinical development, but are challenging to run for simple screening studies in STS mainly due to sample size requirements, and small incentive by phar- maceuticals. Too many randomised controlled phase III trials have recently failed in a rush for success [32]. The development of a new drug might be easier and faster with adaptive randomised trials such as the transformation of a phase II into a phase III (”seamless phase II/III designs”) in case of a positive early stage of a study, or the use of ”drop-the-loser” or ”play-the-winner” designs [17]. Rare tumors require extremely good and innovative trial design to make optimal use of every patient. Importantly, in order to make progress in this context, practice changing decisions will have to be based on less direct evidence than those in common malignancies and all avail- able evidence should be evaluated. With our meta-analyses, we provided new robust benchmarks to speed up the process through single arm studies which are faster to run, and require fewer patients tha...
Future perspectives. The legal perspectives for green leases in Poland are very promising. Interest in these types of agreements is growing. With the increasing ecological awareness of society and the growing number of investors seeking sustainable investments, as well as initiatives such as the European Green Deal, it can also be expected that Polish law will evolve towards promoting green leases. Further statutory regulations on these issues cannot be ruled out either. It should be advocated, however, that new regulations are clear and provide a good incentive for companies to implement ecological practices in the Polish real estate sector.
