Future perspectives. In recent years, both implant design and measurement techniques of implant performance, like implant migration techniques, have improved considerable and in turn have improved implants and thus patient safety and outcomes. Biomarkers for example could monitor or identify implants at risk for loosening. Furthermore, an improvement in implant migration assessment could be the development of CT- based RSA, which has emerged as a promising technique in implant-bone migration assessment.65-68 Last, the introduction of 3D-printing technology has enabled the creation of customized and patient-centred implants, but whether this is favourable in the long run for implant fixation, also has to be shown by implant migration studies.69 An early warning signal Chapter IX As mentioned earlier, TKAs have an excellent survival of approximately 94-96% at ten-years.1, 2 Although the risk of TKA failure is low, it is associated with severe morbidity and frequently results in extensive revision surgery.70 71 This low revision rate in the overall TKA population, but not in the younger population (e.g., 60 years), makes it difficult to improve outcomes. Where RSA can only be used in specific and a limited number of patients, it is frequently only used in patients included in studies. It also requires additional steps intra-operatively, in contrast with other biological markers that could be assessed relatively easy in large patient cohorts. This thesis contributes further evidence by demonstrating that serum tumour necrosis factor α (TNFα), serum interleukin-1b (IL-1b), serum osteocalcin, and urinary N-terminal telopeptide (NTX) were significantly increased in loosened implants compared with stable implants at time of diagnosis or prior to revision surgery (Chapter III). These findings suggest that these biomarkers may have the potential to act as early indicators for loosened implants, as well as for monitoring progression of loosening.72, 73 Advantages of such biomarkers are: first, sampling from patients with implant-related complaints, thus differentiating between implant-bone interface problems (e.g. loosening), soft-tissue problems, infection or other factors. Also, longitudinal studies could establish biomarker values that predict loosening. If the association between specific biomarker levels and implant loosening is further confirmed, these biomarkers could be used to monitor treatment modalities aimed at preventing or delaying implant loosening, like gene- directed the...
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 various studies of this thesis, added to those in the literature, suggested several targets for (further) studies. In addition to the discussion of the previous studies, I will briefly discuss current studies and literature on some of these different targets as a basis for further research. Oxygen flow rates, techniques of oxygen application, breathing patterns and gas temperatures and pressures The beneficial effect of oxygen compared to sublingual ergotamine tartrate and placebo has been shown at flow rates of 7 and 12 L/min, respectively.9, 10 The difference in effect between 7 L/min and 12 L/min, however, has never been investigated in a controlled study. Our current ongoing CLuster headache ATtacks OXYgen Treatment (CLATOXYT) trial (trial ID NTR3801) has the primary objective to study whether there is a difference in treatment effect between these two oxygen flow rates in the acute treatment of CH attacks. This study in newly diagnosed or oxygen naïve adult CH patients, uses a double-blind crossover design, two questionnaires and a diary. At present, approximately 90% of the targeted total number of patients has been included. We recently reviewed the efficacy of the standard non-rebreathing masks with normobaric room temperature oxygen in relieving pain in CH.20 Regarding the fraction of inspired oxygen, interfaces like tusk mask variants are at least similar to the standard non-rebreathing masks, and demand valve oxygen is even superior.20 Currently, only demand valve oxygen (in combination with initial hyperventilation) has been investigated in a pilot study as a new oxygen delivery system for the acute treatment of CH. The number of four participants was too small to draw any firm conclusions,21 although the positive trend suggests requirement of further study in larger patient groups. Although hyperventilation may result in an increase in partial pressure of oxygen, hypocapnia and vasoconstriction,20 the effect of hyperventilation on pain reduction during a CH attack has not been extensively studied. Whether hyperventilation is superior to normal breathing with regard to CH pain reduction is unknown and might require further study. In a study investigating an expected superior role of inhaled gas temperature over oxygen concentration, it was shown that inhalation of room air of 5 °C at a flow rate of 6 L/min for at least 15 min provided significant relief in 85% of eighty treated CH attacks, a result similar to 100% oxygen (with no details pr...
Future perspectives. While much has been learned about the functions and significance of DNA methylation over the last several decades, our current understanding is undergoing rapid revision. The recent discovery that endogenous methylated cytosine residues in mammalian DNA are naturally subject to enzyme-driven oxidation and detection of the oxidized methylcytosine derivatives (hydroxymethylcytosine (hmC), formylcytosine (fC), and carboxycytosine (caC)) in human and mouse DNA has prompted considerable effort to decipher the relative roles of these modified residues in gene expression and genome function [24]. The fC and caC forms serve as substrates for the DNA repair machinery, which removes the oxidized base and replaces it with unmodified cytosine, resulting in a net “demethylation” event, suggesting that DNA methylation patterns may be far more dynamic than previously anticipated. How radiation exposure of any type influences the formation or removal of these modified methylcytosine bases has not yet been explored. Furthermore, DNA methylation patterns are only one component of a broader epigenetic ‘code’ that includes posttranslational modifications to the histone proteins on which the DNA is wound into chromatin. Together, the pattern of DNA methylation and histone modifications helps to organize the genome into domains of different transcriptional potential. While local changes in histone modification status at the site of radiation-induced double strand breaks is known to play an important role in alerting the DNA repair machinery and cell cycle to the presence of DNA damage [25], recent work has suggested that radiation exposure (X-ray) can also influence global levels of various modified histones, suggesting a broader reprogramming of the epigenomic landscape [26]. Methods exist to map the genome-wide patterns of histone modifications as well, and have not yet been applied to high LET radiation exposure. Indeed, it has been argued that an assessment of DNA methylation and other epigenetic modifications should be considered in environmental toxicity and risk assessment, and that an understanding of the specific epigenetic “footprint” left by various chemical or physical toxins could one day be used to monitor a person’s exposure history [7]. The identification of specific and unique DNA methylation changes associated with high-LET radiation and known to be associated with diseases such as cancer, could in principle be used by NASA for ‘biodosimetry’; monitoring the 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. The EU-PolarNet consortium can look back at a wide range of stakeholder interactions. However, the consortium has also identified some aspects that can be improved and some stakeholder groups that should have been engaged more frequently. This will be a task for the remaining project lifespan. Although indigenous communities have been reached at several forums, more effort should be put into incorporating indigenous peoples and local community’s knowledge in the EU-PolarNet research planning process. This is not an easy task because relationships are built up upon trust over long time periods. However, EU-PolarNet is aware of these problems and is increasing its efforts to work with indigenous and local communities. The two indigenous colleagues (a Saami representative and an Inuit representative from Greenland) that were invited, accepted and actively contributed to the white paper process, which can be seen as a first success and demonstrates that established personal contacts are key for lasting and trustful partnerships. EU-PolarNet is also aiming include indigenous representatives in the design of the Integrated Polar Research Programme. We also consider that links with education and capacity building structures should be implemented, since the education is the basis for knowledge and interaction. This could be reinforced through the contacts that members of EU-PolarNet have with educational programmes such as APECS and, UArctic. Industry is well represented among the stakeholders participating in the events, but several sectors of industry have not been addressed by EU-PolarNet yet. In particular, the companies involved in polar research operations (e.g. Kings Bay in the Arctic, or AGUNSA in the Antarctic) might be interested in participating in the co-production process of the integrated European Polar Research programme. Another important group of stakeholders are non-governmental organisations that are very active in the polar regions and represent the civil society. We are aware that NGOs such as WWF and Greenpeace could feed in relevant contributions to the research programme and that we need to make efforts in cooperating closer with them. Although funding agencies, as well as the European Commission, have been involved frequently in the events organized by EU-PolarNet, this is an especially relevant group of stakeholders which should be approached continuously. This interaction might be reinforced, mainly in non-Arctic countries, and personal ...
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. All the above-mentioned universities shall develop the main directions of artistic research, and research groups (laboratories, research centres) shall be established, which involve foreign experts and collaborate with other universities, institutions and companies. In cooperation with the Ministry of Education and Research, the Estonian Research Agency and universities, a sustainable funding model for the development of artistic research shall be developed with a view to both baseline funding and targeted financing, and a research funding system will be established for artistic projects or projects that incorporate artistic research. In order to popularize artistic research, a web platform will be developed in cooperation with universities, which will consolidate materials, publications and project overviews related to artistic research. In cooperation with the Estonian Research Agency and universities, principles, necessary classifications and technical means for recognizing artistic research in the Estonian Research Information System shall be developed. Other documents on artistic research The Vienna Declaration on Artistic Research: xxxxx://xxxxxxxxxxxxxxxxxxx.xxx/files/2020/06/Vienna-Declaration-on-AR_corrected- version_24-June-20-1.pdf Association Européenne des Conservatoires, Académies de Musique et Musikhochschulen: White paper on Artistic Research: xxxxx://xxx.xxx-xxxxx.xx/userfiles/File/Key%20Concepts/White%20Paper%20AR%20- %20Key%20Concepts%20for%20AEC%20Members%20-%20EN.pdf
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. Treosulfan exposure in specific disease types and patient groups 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 pe...
Future perspectives. Almost all publications on FNAIT describe observational studies. Until recently, only the group of Bussel at Cornell University had performed randomised con- trolled trials (RCT). Although our first attempt, with the international NOICH study group, to carry out a large RCT had to be stopped prematurely for not reaching the required sample size, we do consider this trial a successful pilot study. In the participating centres, practically all patients consented to be randomised, almost all received and completed the assigned treatment and none were lost to follow-up. The single reason for not completing the study within a reasonable time frame was the limited number of centres participating. We do therefore be- lieve that in the future, adequately powered RCT’s in this field are certainly pos- sible, provided that a large number of centres in many countries together agree to commit to collaboration. Based on our experience with the NOICH trial, we regard the following prereq- uisites to be fulfilled in order to expect such RCT’s to become a success: • Clinical relevance of the study question clear to all potential participants • Willingness to go through the invariably time-consuming IRB approval process for a usually very limited number of patients that each centre can contribute • Adequate funding for all additional work, including laboratory, mailing and data-entering expenses • One dedicated research person in each participating centre with enough time, motivation and alertness to ensure that the few eligible patients per year are not missed, are informed in time, are randomised and are followed according to protocol. • Web-based randomisation and easy to use study database. These items may all seem straightforward. One has to realise however that apart from a few centres around the world in countries with a high level of centrali- 138 chapter 10 general discussion and future perspectives sation, most centres see less than five FNAIT pregnancies per year. For most, this particular disease, however devastating it can be, is not one of their main interests in terms of fetal medicine research. To still collaborate in studies with FNAIT patients, participation must be made very easy and as attractive as pos- sible. This remains a challenge, however, we feel that, based on our many contact with colleagues around the world, it should be possible to carry out relatively large prospective studies and RCT’s with FNAIT patients. There may be a role for existing F...
