Improvements of the doubled haploid technology in maize

The in vivo doubled haploid (DH) technology in maize carries many advantages over traditional line development by recurrent selfing and has played an integral role in numerous breeding programs since the early 21st century. A bottleneck in the DH technology is still the success rate of chromosome doubling treatment, which has a strong influence on the costs of DH production. Currently, only a minority (~10%) of treated D0 haploid plants result in DH lines. Improvement in the chromosome doubling step of DH production would not only make DH lines cheaper, but could also change the optimum allocation of resources in hybrid breeding. In addition, the development of treatments using alternative doubling agents to colchicine, which is toxic to humans, would improve worker safety and simplify waste disposal issues for developing countries to benefit from the DH technology. Initiating such developments is the goal of this thesis. In a first step, we evaluated anti-mitotic herbicides with different modes of action as alternatives to colchicine for reducing the toxicity of chromosome-doubling treatment and for potentially increasing the success rates. In a series of experiments, we evaluated anti-mitotic herbicides with different modes of action in different concentrations and combinations. Based on the results of the initial experiments, we chose a specific concentration of amiprophos-methyl for evaluation in combination with varying concentrations of pronamide in a further experiment. This revealed the optimal concentration of pronamide in combination with the chosen concentration of amiprophos-methyl. However, this less-toxic treatment showed slightly lower success rates and slightly higher costs per DH line as compared to the standard colchicine treatment. In a second step after evaluating anti-mitotic herbicides for seedling treatment, we evaluated gaseous treatments using nitrous oxide (N2O), an anti-mitotic gas, in varying concentrations and combinations with air and pure oxygen. In two years of evaluation, we found an N2O treatment which had similar success rates as colchicine. The major benefit of such treatment is that this gas can simply be released into the atmosphere, eliminating the difficulty of proper chemical waste disposal, which is difficult to secure in developing countries. The only requirement is a treatment chamber, in contrast to the laboratory facilities required for handling colchicine. In a third step, we evaluated the potential of spontaneous chromosome doubling (SCD) as an alternative to chemical treatment-based chromosome doubling. Although previous studies found significant genetic variation and high heritability for SCD, a classical quantitative genetic analysis, elucidating the type of gene action governing this trait, and a selection experiment for improving SCD was missing in the literature. We found a predominance of additive genetic effects compared to epistatic effects, and a large selection gain after three cycles of recurrent selection for SCD to levels far beyond those reached by standard colchicine treatment. This indicates the great potential of SCD to improve the DH technology. The approximately ten-fold increase in spontaneous chromosome doubling rate (SDR) reached in our recurrent selection experiment marks a paradigm shift in the chromosome doubling step of DH production in maize. DH production efficiency can be greatly increased by the vast improvement in SDR, and production can be further simplified to enable even higher throughput. Instead of chromosome doubling treatment, which involves much handling of seedlings, haploid seeds from germplasm with a high innate ability to produce seed set without chemical treatment can be simply seeded in the DH nursery, eliminating the most costly production steps. Thus, this thesis has provided new opportunities to increase worker safety and reduce toxic waste in DH production, and further provided a proof of concept for genetic improvement of spontaneous chromosome doubling, which has great prospects for increasing the efficiency of DH production in maize.Die in vivo Methode zur Erzeugung von Doppelhaploiden (DH) bei Mais bietet wesentliche Vorteile gegenüber der traditionellen Produktion von reinerbigen Inzuchtlinien mittels rekurrenter Selbstung und ist mittlerweile integraler Bestandteil vieler Maisuchtprogramme in den gemäßigten Anbauzonen. In der DH-Technologie besteht jedoch ein großer Bedarf, die Erfolgsraten bei der Behandlung zur Aufdopplung des Chromosomensatzes zu steigern, da bislang nur bei einem bescheidenen Prozentsatz (~10%) behandelter haploider Keimlinge fertile D0-Pflanzen erzeugt werden können und dies substantiell die Kosten der DH-Produktion bestimmt. Verbesserungen dieses Schrittes der Produktion von DH-Linien haben neben einer Kostenersparnis auch Auswirkungen auf die optimale Allokation von Ressourcen in der Hybridzüchtung. Die Nutzung alternativer Aufdopplungsverfahren, insbesondere die Verwendung alternativer Wirkstoffe zu dem bislang üblichen hochtoxischen Colchicin, bergen erhebliche Vorteile für den Arbeitsschutz und eine einfachere Chemikalienentsorgung. Derartige Fortschritte könnten den Einsatz der DH-Technologie insbesondere in Entwicklungsländern befördern. Ziel der vorliegenden Arbeit war es, diese Entwicklungen durch Suche nach alternativen Aufdoppelungsverfahren voranzutreiben. Als erster Schritt wurden in einer Versuchsreihe anti-mitotische Herbizide mit unterschiedlichen Wirkungsweisen und Konzentrationen als Alternative zu Colchicin untersucht, um einerseits die toxische Gefährdung bei der Behandlung zur Chromosomen-Aufdopplung zu reduzieren und andererseits die Erfolgsrate zu erhöhen. Basierend auf den Ergebnissen aus ersten Experimenten wurde in einem weiteren Experiment eine Konzentrationssteigerung von Pronamid in Kombination mit Amiprophos-methyl untersucht und eine optimale Applikation beider Chemikalien gefunden. Diese zeigte eine nur marginal geringere Erfolgsrate bei kaum höheren Kosten pro erzeugter DH-Linie im Vergleich zur bisherigen Standardmethode mittels Colchicin. Als zweiter Schritt wurden gasförmige Behandlungen mit Distickstoffmonoxid (N2O), einem antimitotischem Gas, in verschiedenen Konzentrationen und Kombinationen mit Luft oder reinem Sauerstoff getestet. Mittels der zweijährigen Untersuchungsreihe konnte gezeigt werden, dass Behandlung mit N2O eine ähnliche Erfolgsrate hat wie Colchicin. Der große Vorteil der Lachgasbehandlung gegenüber Colchicin besteht darin, dass das Gas nach der Nutzung in die Atmosphäre entlassen werden kann und keine aufwendige chemische Abfallentsorgung notwendig ist, was in Entwicklungsländern meist nicht garantiert werden kann. Zur Behandlung haploider Keimlinge ist lediglich ein Druckbehälter und das Gas erforderlich, jedoch anders als im Umgang mit Colchicin kein speziell ausgestattetes Labor. In einem dritten Schritt wurde die spontane Chromosomen-Aufdopplung (spontaneous chromosome doubling; SCD) als Alternative zur chemischen Behandlung untersucht. Während bisherige Arbeiten große genetische Unterschiede sowie eine hohe Heritabilität für SCD fanden, fehlten bislang klassische quantitativ-genetische Untersuchungen, um die genetische Architektur von SCD zu analysieren. In dieser Arbeit wurde gezeigt, dass SCD vornehmlich auf additiven Geneffekten beruht und weniger auf epistatischen Effekten. In einem erstmals durchgeführten Selektionsexperiment zur Verbesserung der SCD konnte bereits nach drei Generationen rekurrenter Selektion ein erheblicher Selektionserfolg erreicht werden. Damit wurde die spontane Aufdopplungsrate (spontaneous doubling rate; SDR) auf ein Niveau gebracht, welche den Erfolg der Standardmethode basierend auf der Behandlung mit Colchicin weit übertraf. Die im Vergleich zu dem Ausgangsniveau des Zuchtmaterials um den Faktor 10 erhöhte SCD, die in unserem rekurrenten Selektionsexperiment erreicht werden konnte, markiert einen Paradigmenwechsel in einem für die DH-Technik wichtigen Schritt. Erheblich höhere SDR verbessern die Effizienz der DH-Produktion und vereinfachen diese zugleich. Denn anstatt der Behandlung von Keimlingen mit Colchicin können haploide Körner mit hoher SDR direkt im Zuchtgarten ausgesät werden und damit der arbeitsintensivste und zugleich teuerste Schritt der DH-Produktion umgangen werden. Insgesamt zeigt die vorliegende Arbeit verschiedene neue, erfolgsversprechende Möglichkeiten auf, um den obligatorischen Schritt der Chromosomen-Aufdopplung effizienter zu gestalten und somit die DH-Produktion von reinerbigen Linien in der Maiszüchtung zu verbessern

Improvements of the doubled haploid technology in maize

The in vivo doubled haploid (DH) technology in maize carries many advantages over traditional line development by recurrent selfing and has played an integral role in numerous breeding programs since the early 21st century. A bottleneck in the DH technology is still the success rate of chromosome doubling treatment, which has a strong influence on the costs of DH production. Currently, only a minority (~10%) of treated D0 haploid plants result in DH lines. Improvement in the chromosome doubling step of DH production would not only make DH lines cheaper, but could also change the optimum allocation of resources in hybrid breeding. In addition, the development of treatments using alternative doubling agents to colchicine, which is toxic to humans, would improve worker safety and simplify waste disposal issues for developing countries to benefit from the DH technology. Initiating such developments is the goal of this thesis. In a first step, we evaluated anti-mitotic herbicides with different modes of action as alternatives to colchicine for reducing the toxicity of chromosome-doubling treatment and for potentially increasing the success rates. In a series of experiments, we evaluated anti-mitotic herbicides with different modes of action in different concentrations and combinations. Based on the results of the initial experiments, we chose a specific concentration of amiprophos-methyl for evaluation in combination with varying concentrations of pronamide in a further experiment. This revealed the optimal concentration of pronamide in combination with the chosen concentration of amiprophos-methyl. However, this less-toxic treatment showed slightly lower success rates and slightly higher costs per DH line as compared to the standard colchicine treatment. In a second step after evaluating anti-mitotic herbicides for seedling treatment, we evaluated gaseous treatments using nitrous oxide (N2O), an anti-mitotic gas, in varying concentrations and combinations with air and pure oxygen. In two years of evaluation, we found an N2O treatment which had similar success rates as colchicine. The major benefit of such treatment is that this gas can simply be released into the atmosphere, eliminating the difficulty of proper chemical waste disposal, which is difficult to secure in developing countries. The only requirement is a treatment chamber, in contrast to the laboratory facilities required for handling colchicine. In a third step, we evaluated the potential of spontaneous chromosome doubling (SCD) as an alternative to chemical treatment-based chromosome doubling. Although previous studies found significant genetic variation and high heritability for SCD, a classical quantitative genetic analysis, elucidating the type of gene action governing this trait, and a selection experiment for improving SCD was missing in the literature. We found a predominance of additive genetic effects compared to epistatic effects, and a large selection gain after three cycles of recurrent selection for SCD to levels far beyond those reached by standard colchicine treatment. This indicates the great potential of SCD to improve the DH technology. The approximately ten-fold increase in spontaneous chromosome doubling rate (SDR) reached in our recurrent selection experiment marks a paradigm shift in the chromosome doubling step of DH production in maize. DH production efficiency can be greatly increased by the vast improvement in SDR, and production can be further simplified to enable even higher throughput. Instead of chromosome doubling treatment, which involves much handling of seedlings, haploid seeds from germplasm with a high innate ability to produce seed set without chemical treatment can be simply seeded in the DH nursery, eliminating the most costly production steps. Thus, this thesis has provided new opportunities to increase worker safety and reduce toxic waste in DH production, and further provided a proof of concept for genetic improvement of spontaneous chromosome doubling, which has great prospects for increasing the efficiency of DH production in maize.Die in vivo Methode zur Erzeugung von Doppelhaploiden (DH) bei Mais bietet wesentliche Vorteile gegenüber der traditionellen Produktion von reinerbigen Inzuchtlinien mittels rekurrenter Selbstung und ist mittlerweile integraler Bestandteil vieler Maisuchtprogramme in den gemäßigten Anbauzonen. In der DH-Technologie besteht jedoch ein großer Bedarf, die Erfolgsraten bei der Behandlung zur Aufdopplung des Chromosomensatzes zu steigern, da bislang nur bei einem bescheidenen Prozentsatz (~10%) behandelter haploider Keimlinge fertile D0-Pflanzen erzeugt werden können und dies substantiell die Kosten der DH-Produktion bestimmt. Verbesserungen dieses Schrittes der Produktion von DH-Linien haben neben einer Kostenersparnis auch Auswirkungen auf die optimale Allokation von Ressourcen in der Hybridzüchtung. Die Nutzung alternativer Aufdopplungsverfahren, insbesondere die Verwendung alternativer Wirkstoffe zu dem bislang üblichen hochtoxischen Colchicin, bergen erhebliche Vorteile für den Arbeitsschutz und eine einfachere Chemikalienentsorgung. Derartige Fortschritte könnten den Einsatz der DH-Technologie insbesondere in Entwicklungsländern befördern. Ziel der vorliegenden Arbeit war es, diese Entwicklungen durch Suche nach alternativen Aufdoppelungsverfahren voranzutreiben. Als erster Schritt wurden in einer Versuchsreihe anti-mitotische Herbizide mit unterschiedlichen Wirkungsweisen und Konzentrationen als Alternative zu Colchicin untersucht, um einerseits die toxische Gefährdung bei der Behandlung zur Chromosomen-Aufdopplung zu reduzieren und andererseits die Erfolgsrate zu erhöhen. Basierend auf den Ergebnissen aus ersten Experimenten wurde in einem weiteren Experiment eine Konzentrationssteigerung von Pronamid in Kombination mit Amiprophos-methyl untersucht und eine optimale Applikation beider Chemikalien gefunden. Diese zeigte eine nur marginal geringere Erfolgsrate bei kaum höheren Kosten pro erzeugter DH-Linie im Vergleich zur bisherigen Standardmethode mittels Colchicin. Als zweiter Schritt wurden gasförmige Behandlungen mit Distickstoffmonoxid (N2O), einem antimitotischem Gas, in verschiedenen Konzentrationen und Kombinationen mit Luft oder reinem Sauerstoff getestet. Mittels der zweijährigen Untersuchungsreihe konnte gezeigt werden, dass Behandlung mit N2O eine ähnliche Erfolgsrate hat wie Colchicin. Der große Vorteil der Lachgasbehandlung gegenüber Colchicin besteht darin, dass das Gas nach der Nutzung in die Atmosphäre entlassen werden kann und keine aufwendige chemische Abfallentsorgung notwendig ist, was in Entwicklungsländern meist nicht garantiert werden kann. Zur Behandlung haploider Keimlinge ist lediglich ein Druckbehälter und das Gas erforderlich, jedoch anders als im Umgang mit Colchicin kein speziell ausgestattetes Labor. In einem dritten Schritt wurde die spontane Chromosomen-Aufdopplung (spontaneous chromosome doubling; SCD) als Alternative zur chemischen Behandlung untersucht. Während bisherige Arbeiten große genetische Unterschiede sowie eine hohe Heritabilität für SCD fanden, fehlten bislang klassische quantitativ-genetische Untersuchungen, um die genetische Architektur von SCD zu analysieren. In dieser Arbeit wurde gezeigt, dass SCD vornehmlich auf additiven Geneffekten beruht und weniger auf epistatischen Effekten. In einem erstmals durchgeführten Selektionsexperiment zur Verbesserung der SCD konnte bereits nach drei Generationen rekurrenter Selektion ein erheblicher Selektionserfolg erreicht werden. Damit wurde die spontane Aufdopplungsrate (spontaneous doubling rate; SDR) auf ein Niveau gebracht, welche den Erfolg der Standardmethode basierend auf der Behandlung mit Colchicin weit übertraf. Die im Vergleich zu dem Ausgangsniveau des Zuchtmaterials um den Faktor 10 erhöhte SCD, die in unserem rekurrenten Selektionsexperiment erreicht werden konnte, markiert einen Paradigmenwechsel in einem für die DH-Technik wichtigen Schritt. Erheblich höhere SDR verbessern die Effizienz der DH-Produktion und vereinfachen diese zugleich. Denn anstatt der Behandlung von Keimlingen mit Colchicin können haploide Körner mit hoher SDR direkt im Zuchtgarten ausgesät werden und damit der arbeitsintensivste und zugleich teuerste Schritt der DH-Produktion umgangen werden. Insgesamt zeigt die vorliegende Arbeit verschiedene neue, erfolgsversprechende Möglichkeiten auf, um den obligatorischen Schritt der Chromosomen-Aufdopplung effizienter zu gestalten und somit die DH-Produktion von reinerbigen Linien in der Maiszüchtung zu verbessern

All-optical octave-broad ultrafast switching of Si woodpile photonic band gap crystals

We present ultrafast all-optical switching measurements of Si woodpile photonic band gap crystals. The crystals are spatially homogeneously excited and probed by measuring reflectivity over an octave in frequency (including the telecommunication range) as a function of time. After 300 fs, the complete stop band has shifted to higher frequencies as a result of optically excited free carriers. The switched state relaxes quickly with a time constant of 18 ps. We present a quantitative analysis of switched spectra with theory for finite photonic crystals. The induced changes in refractive index are well described by a Drude model with a carrier relaxation time of 10 fs. We briefly discuss possible applications of high-repetition-rate switching of photonic crystal cavities

Functional identification in Lactobacillus reuteri of a PocR-like transcription factor regulating glycerol utilization and vitamin B12 synthesis

<p>Abstract</p> <p>Background</p> <p><it>Lactobacillus reuteri </it>harbors the genes responsible for glycerol utilization and vitamin B₁₂synthesis within a genetic island phylogenetically related to gamma-Proteobacteria. Within this island, resides a gene (<it>lreu_1750</it>) that based on its genomic context has been suggested to encode the regulatory protein PocR and presumably control the expression of the neighboring loci. However, this functional assignment is not fully supported by sequence homology, and hitherto, completely lacks experimental confirmation.</p> <p>Results</p> <p>In this contribution, we have overexpressed and inactivated the gene encoding the putative PocR in <it>L. reuteri</it>. The comparison of these strains provided metabolic and transcriptional evidence that this regulatory protein controls the expression of the operons encoding glycerol utilization and vitamin B₁₂synthesis.</p> <p>Conclusions</p> <p>We provide clear experimental evidence for assigning Lreu_1750 as PocR in <it>Lactobacillus reuteri</it>. Our genome-wide transcriptional analysis further identifies the loci contained in the PocR regulon. The findings reported here could be used to improve the production-yield of vitamin B₁₂, 1,3-propanediol and reuterin, all industrially relevant compounds.</p

Implementation of contemporary chemotherapy for patients with metastatic pancreatic ductal adenocarcinoma: a population-based analysis

Background: Positive results of randomized trials led to the introduction of FOLFIRINOX in 2012 and gemcitabine with nab-paclitaxel in 2015 for patients with metastatic pancreatic ductal adenocarcinoma. It is unknown to which extent these new chemotherapeutic regimens have been implemented in clinical practice and what the impact has been on overall survival. Material and methods: Patients diagnosed with metastatic pancreatic ductal adenocarcinoma between 2007–2016 were included from the population-based Netherlands Cancer Registry. Multilevel logistic regression and Cox regression analyses, adjusting for patient, tumor, and hospital characteristics, were used to analyze variation of chemotherapy use. Results: In total, 8726 patients were included. The use of chemotherapy increased from 31% in 2007–2011 to 37% in 2012–2016 (p <.001). Variation in the use of any chemotherapy between centers decreased (adjusted range 2007–2011: 12–67%, 2012–2016: 20–54%) whereas overall survival increased from 5.6 months to 6.4 months (p <.001) for patients treated with chemotherapy. Use of FOLFIRINOX and gemcitabine with nab-paclitaxel varied widely in 2015–2016, but both showed a more favorable overall survival compared to gemcitabine monotherapy (median 8.0 vs. 7.0 vs. 3.8 months, respectively). In the period 2015–2016, FOLFIRINOX was used in 60%, gemcitabine with nab-paclitaxel in 9.7% and gemcitabine monotherapy in 25% of patients receiving chemotherapy. Conclusion: Nationwide variation in the use of chemotherapy decreased after the implementation of FOLFIRINOX and gemcitabine with nab-paclitaxel. Still a considerable proportion of patients receives gemcitabine monotherapy. Overall survival did improve, but not clinically relevant. These results emphasize the need for a structured implementation of new chemotherapeutic regimens

Immediate versus postponed intervention for infected necrotizing pancreatitis

BACKGROUND Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown. METHODS We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up. RESULTS A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, −1; 95% confidence interval [CI], −12 to 10; P=0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups. CONCLUSIONS This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions

Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer:A multicenter prospective cohort

Introduction: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC. Materials and methods: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy. Results: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34). Conclusion: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice. (C) 2020 The Authors. Published by Elsevier Ltd

Intervention mapping for development of a participatory return-to-work intervention for temporary agency workers and unemployed workers sick-listed due to musculoskeletal disorders

BACKGROUND: In the past decade in activities aiming at return-to-work (RTW), there has been a growing awareness to change the focus from sickness and work disability to recovery and work ability. To date, this process in occupational health care (OHC) has mainly been directed towards employees. However, within the working population there are two vulnerable groups: temporary agency workers and unemployed workers, since they have no workplace/employer to return to, when sick-listed. For this group there is a need for tailored RTW strategies and interventions. Therefore, this paper aims to describe the structured and stepwise process of development, implementation and evaluation of a theory- and practise-based participatory RTW program for temporary agency workers and unemployed workers, sick-listed due to musculoskeletal disorders (MSD). This program is based on the already developed and cost-effective RTW program for employees, sick-listed due to low back pain. METHODS: The Intervention Mapping (IM) protocol was used to develop a tailor-made RTW program for temporary agency workers and unemployed workers, sick-listed due to MSD. The Attitude-Social influence-self-Efficacy (ASE) model was used as a theoretical framework for determinants of behaviour regarding RTW of the sick-listed worker and development of the intervention. To ensure participation and facilitate successful adoption and implementation, important stakeholders were involved in all steps of program development and implementation. Results of semi-structured interviews and 'fine-tuning' meetings were used to design the final participatory RTW program. RESULTS: A structured stepwise RTW program was developed, aimed at making a consensus-based RTW implementation plan. The new program starts with identifying obstacles for RTW, followed by a brainstorm session in which the sick-listed worker and the labour expert of the Social Security Agency (SSA) formulate solutions/possibilities for suitable (therapeutic) work. This process is guided by an independent RTW coordinator to achieve consensus. Based on the resulting RTW implementation plan, to create an actual RTW perspective, a vocational rehabilitation agency is assigned to find a matching (therapeutic) workplace. The cost-effectiveness of this participatory RTW program will be evaluated in a randomised controlled trial. CONCLUSION: IM is a promising tool for the development of tailor-made OHC interventions for the vulnerable working populatio

Nationwide comprehensive gastro-intestinal cancer cohorts: the 3P initiative

Background: The increasing sub-classification of cancer patients due to more detailed molecular classification of tumors, and limitations of current trial designs, require innovative research designs. We present the design, governance and current standing of three comprehensive nationwide cohorts including pancreatic, esophageal/gastric, and colorectal cancer patients (NCT02070146). Multidisciplinary collection of clinical data, tumor tissue, blood samples, and patient-reported outcome (PRO) measures with a nationwide coverage, provides the infrastructure for future and novel trial designs and facilitates research to improve outcomes of gastrointestinal cancer patients. Material and methods: All patients aged ≥18 years with pancreatic, esophageal/gastric or colorectal cancer are eligible. Patients provide informed consent for: (1) reuse of clinical data; (2) biobanking of primary tumor tissue; (3) collection of blood samples; (4) to be informed about relevant newly identified genomic aberrations; (5) collection of longitudinal PROs; and (6) to receive information on new interventional studies and possible participation in cohort multiple randomized controlled trials (cmRCT) in the future. Results: In 2015, clinical data of 21,758 newly diagnosed patients were collected in the Netherlands Cancer Registry. Additional clinical data on the surgical procedures were registered in surgical audits for 13,845 patients. Within the first two years, tumor tissue and blood samples were obtained from 1507 patients; during this period, 1180 patients were included in the PRO registry. Response rate for PROs was 90%. The consent rate to receive information on new interventional studies and possible participation in cmRCTs in the future was >85%. The number of hospitals participating in the cohorts is steadily increasing. Conclusion: A comprehensive nationwide multidisciplinary gastrointestinal cancer cohort is feasible and surpasses the limitations of classical study designs. With this initiative, novel and innovative studies can be performed in an efficient, safe, and comprehensive setting