FMRI Effective Connectivity and TMS Chronometry: Complementary Accounts of Causality in the Visuospatial Judgment Network

BACKGROUND: While traditionally quite distinct, functional neuroimaging (e.g. functional magnetic resonance imaging: fMRI) and functional interference techniques (e.g. transcranial magnetic stimulation: TMS) increasingly address similar questions of functional brain organization, including connectivity, interactions, and causality in the brain. Time-resolved TMS over multiple brain network nodes can elucidate the relative timings of functional relevance for behavior ("TMS chronometry"), while fMRI functional or effective connectivity (fMRI EC) can map task-specific interactions between brain regions based on the interrelation of measured signals. The current study empirically assessed the relation between these different methods. METHODOLOGY/PRINCIPAL FINDINGS: One group of 15 participants took part in two experiments: one fMRI EC study, and one TMS chronometry study, both of which used an established cognitive paradigm involving one visuospatial judgment task and one color judgment control task. Granger causality mapping (GCM), a data-driven variant of fMRI EC analysis, revealed a frontal-to-parietal flow of information, from inferior/middle frontal gyrus (MFG) to posterior parietal cortex (PPC). FMRI EC-guided Neuronavigated TMS had behavioral effects when applied to both PPC and to MFG, but the temporal pattern of these effects was similar for both stimulation sites. At first glance, this would seem in contradiction to the fMRI EC results. However, we discuss how TMS chronometry and fMRI EC are conceptually different and show how they can be complementary and mutually constraining, rather than contradictory, on the basis of our data. CONCLUSIONS/SIGNIFICANCE: The findings that fMRI EC could successfully localize functionally relevant TMS target regions on the single subject level, and conversely, that TMS confirmed an fMRI EC identified functional network to be behaviorally relevant, have important methodological and theoretical implications. Our results, in combination with data from earlier studies by our group (Sack et al., 2007, Cerebral Cortex), lead to informed speculations on complex brain mechanisms, and TMS disruption thereof, underlying visuospatial judgment. This first in-depth empirical and conceptual comparison of fMRI EC and TMS chronometry thereby shows the complementary insights offered by the two methods

Long-term second primary cancer risk in adolescent and young adult (15-39 years) cancer survivors:a population-based study in the Netherlands between 1989 and 2018

Background: Few studies have comprehensively investigated the long-term second cancer risk among adolescent and young adult (AYA, aged 15-39 years) cancer survivors. This study investigated the long-term second cancer risk by including the full range of first and second cancer combinations with at least 10 observations in the Netherlands between 1989 and 2018. Materials and methods: First and second primary cancer data of all 6-month AYA cancer survivors were obtained from the nationwide population-based Netherlands Cancer Registry. Excess cancer risk compared to the general population was assessed with standardized incidence ratio (SIR) and absolute excess risk (AER) statistics up to 25 years after diagnosis. Cumulative incidences were estimated, using death as a competing risk factor. Analyses were carried out with and without applying multiple cancer rules. Results: The cohort included 99 502 AYA cancer survivors. Male survivors had a 2-fold higher risk of developing any cancer compared to the general population, whereas this was around 1.3-fold in females. AERs were 17.5 and 10.1 per 10 000 person-years for males and females. The long-term excess risk of cancer was significantly higher for most first and second primary cancer combinations, but comparable and lower risk estimates were also observed. Application of the multiple cancer rules resulted in a noticeable risk underestimation in melanoma, testicular, and breast cancer survivors. Risk outcomes remained similar in most cases otherwise. The cumulative incidence of second cancer overall increased over time up to 8.9% in males and 10.3% in females at 25 years’ follow-up. Highest long-term cumulative incidences were observed among lymphoma survivors (13.3% males and 18.9% females). Conclusions: AYA cancer survivors have a higher cancer risk compared to the general population for most cancers up to 25 years after their initial cancer diagnosis. Additional studies that investigate risk factors for the specific cancer type combinations are needed to develop personalized follow-up strategies.</p

Long-term second primary cancer risk in adolescent and young adult (15-39 years) cancer survivors:a population-based study in the Netherlands between 1989 and 2018

Background: Few studies have comprehensively investigated the long-term second cancer risk among adolescent and young adult (AYA, aged 15-39 years) cancer survivors. This study investigated the long-term second cancer risk by including the full range of first and second cancer combinations with at least 10 observations in the Netherlands between 1989 and 2018. Materials and methods: First and second primary cancer data of all 6-month AYA cancer survivors were obtained from the nationwide population-based Netherlands Cancer Registry. Excess cancer risk compared to the general population was assessed with standardized incidence ratio (SIR) and absolute excess risk (AER) statistics up to 25 years after diagnosis. Cumulative incidences were estimated, using death as a competing risk factor. Analyses were carried out with and without applying multiple cancer rules. Results: The cohort included 99 502 AYA cancer survivors. Male survivors had a 2-fold higher risk of developing any cancer compared to the general population, whereas this was around 1.3-fold in females. AERs were 17.5 and 10.1 per 10 000 person-years for males and females. The long-term excess risk of cancer was significantly higher for most first and second primary cancer combinations, but comparable and lower risk estimates were also observed. Application of the multiple cancer rules resulted in a noticeable risk underestimation in melanoma, testicular, and breast cancer survivors. Risk outcomes remained similar in most cases otherwise. The cumulative incidence of second cancer overall increased over time up to 8.9% in males and 10.3% in females at 25 years’ follow-up. Highest long-term cumulative incidences were observed among lymphoma survivors (13.3% males and 18.9% females). Conclusions: AYA cancer survivors have a higher cancer risk compared to the general population for most cancers up to 25 years after their initial cancer diagnosis. Additional studies that investigate risk factors for the specific cancer type combinations are needed to develop personalized follow-up strategies.</p

The Erasmus Computing Grid – Building a Super-Computer for Free

Today advances in scientific research as well as clinical diagnostics and treatment are inevitably connected with information solutions concerning computation power and information storage. The needs for information technology are enormous and are in many cases the limiting factor for new scientific results or clinical diagnostics and treatment. At the Hogeschool Rotterdam and the Erasmus MC there is a massive need for computation power on a scale of 10,000 to 15,000 computers equivalent to ~20 to ~30 Tflops (1012 floating point operations per second) for a variety of work areas ranging from e.g. MRI and CT scan and microscopic image anlysis to DNA sequence analysis, protein and other structural simulations and analysis. Both institutions have already 13,000 computers, i.e. ~18 Tflops of computer power, available! To make the needed computer power accessible, we started to build the Erasmus Computing Grid (ECG), which is connecting local computers in each institution via central management systems. The system guaranties security and any privacy rules through the used software as well as through our set-up and a NAN and ISO certification process being under way. Similar systems run already world-wide on entire institutions including secured environments like government institutions or banks. Currently, the ECG has a computational power of ~5 Tflops and is one of or already the largest desktop grid in the world. At the Hogeschool Rotterdam meanwhile all computers were included in the ECG. Currently, 10 departments with ~15 projects at the Erasmus MC depend on using the ECG and are preparing or prepared their analysis programs or are already in production state. The Erasmus Computing Grid office and an advisory and control board were set-up. To sustain the ECG now further infrastructure measures have to be taken. Central hardware and specialist personal needs to be put in place for capacity, security and usability reasons for the application at Erasmus MC. This is also necessary in respect to NAN and ISO certification towards diagnostic and commercial ECG use, for which there is great need and potential. Beyond the link to the Dutch BigGrid Initiative and the German MediGRID should be prepared for and realized due to the great interest for cooperation. There is also big political interest from the government to relieve the pressure on computational needs in The Netherlands and to strengthen the Dutch position in the field of high performance computing. In both fields the ECG should be brought into a leading position by establishing the Erasmus MC a centre of excellence for high-performance computing in the medical field in respect to Europe and world-wide. Consequently, we successfully started to build a super-computer at the Hogeschool Rotterdam and Erasmus MC with great opportunities for scientific research, clinical diagnostics and research as well as student training. This will put both institutions in the position to play a major world-wide role in high-performance computing. This will open entire new possibilities for both institutions in terms of recognition and new funding possibilities and is of major importance for The Netherlands and the EU

Financial difficulties experienced by patients with gastrointestinal stromal tumours (GIST) in the Netherlands:data from a cross-sectional multicentre study

Purpose: This study aims to (1) explore the prevalence of patient-reported financial difficulties among GIST patients, differentiating between those currently undergoing tyrosine kinase inhibitor (TKI) treatment and those who are not; (2) investigate associations between financial difficulties and sociodemographic and clinical characteristics, work, cancer-related concerns, anxiety and depression and (3) study the impact of financial difficulties on health-related quality of life. Methods:A cross-sectional study was conducted among Dutch GIST patients diagnosed between 2008 and 2018, who were invited to complete a one-time survey between September 2020 and June 2021. Patients completed nine items of the EORTC item bank regarding financial difficulties, seven work-related questions, the Hospital Anxiety and Depression Scale, Cancer Worry Scale and EORTC QLQ-C30. Results: In total, 328 GIST patients participated (response rate 63.0%), of which 110 (33.8%) were on TKI treatment. Patients currently treated with TKIs reported significantly more financial difficulties compared to patients not on TKIs (17.3% vs 8.7%, p = 0.03). The odds of experiencing financial difficulties was 18.9 (95% CI 1.7–214.7, p = 0.02) times higher in patients who were less able to work due to their GIST diagnosis. Patients who experienced financial difficulties had significantly lower global quality of life and functioning, and more frequently reported psychological symptoms as compared to patients who did not report financial difficulties.Conclusion: Even in a country where the costs of TKIs and follow-up care are covered by health insurance, financial difficulties can be present in GIST patients, especially in patients on TKI treatment, and may negatively influence the quality of life.</p

The association of having a monitoring or blunting coping style with psychological distress, health-related quality of life and satisfaction with healthcare in gastrointestinal stromal tumour (GIST) patients

Background: There are two main coping styles regarding information seeking under medical threat; monitoring (information-seeking) and blunting (information-avoiding). The aim of this study is to (1) determine factors associated with a monitoring or blunting coping style in gastro-intestinal stromal tumour (GIST) patients and (2) investigate its association with psychological distress, cancer-related concerns, health-related quality of life and satisfaction with healthcare. Methods: In a cross-sectional study, Dutch GIST patients completed the shortened version of the Threatening Medical Situations Inventory to determine their coping style, the Hospital Anxiety and Depression Scale, Cancer Worry Scale, EORTC QLQ-C30 and part of the EORTC QLQ-INFO25. Results: A total of 307 patients were classified as blunters (n = 175, 57%) or monitors (n = 132, 43%). Coping style was not associated with tumour or treatment variables, but being a female (OR 2.5; 95%CI 1.5–4.1; p= &lt;.001) and higher educated (OR 5.5; 95%CI 2.5–11.9, p= &lt;.001) were associated with higher odds of being a monitor. Monitors scored significantly lower on emotional functioning (mean = 86.8 vs mean = 90.9, p=.044), which is considered a trivial difference, more often experienced severe fear of cancer recurrence or progression (53.0% vs 37.7%, p=.007), and had more concerns about dying from GIST in the future (60.6% vs 47.4%, p=.025). Compared to blunters, monitors were less satisfied with the received healthcare and information, and would have liked to receive more information.Conclusion: GIST patients with a monitoring coping style experience a higher emotional burden. Additionally, monitors exhibit a greater need for information. Although this need for information could potentially result in fears and concerns, recognising it may also create an opening for tailored communication and information.</p

Health-related quality of life after isolated limb perfusion compared to extended resection, or amputation for locally advanced extremity sarcoma:Is a limb salvage strategy worth the effort?

Introduction: The aim of this study was to compare long-term patient reported outcomes (PROs) in patients with locally advanced extremity soft tissue sarcoma (eSTS) after isolated limb perfusion followed by resection (IR), compared to extended resection (ER), primary amputation (A) or secondary amputation after IR (IR-A). Methods: Patients were selected from the respondents of a multi-institutional cross-sectional cohort survivorship study (SURVSARC) conducted among sarcoma survivors registered in the Netherlands Cancer Registry (NCR), 2–10 years after diagnosis. Used PROs were the EORTC QLQ-C30, the Cancer worry scale (CWS), the Hospital Anxiety and Depression Scale (HADS), and the Toronto Extremity Salvage Score (TESS). Results: We identified 97 eSTS survivors: IR = 20, ER = 49, A = 20, IR-A = 8. While there were no differences in PROs between IR and ER, results showed better functioning and functionality in both groups versus the amputation groups. The amputation groups scored significantly lower on physical functioning (A = 62.7, IR-A = 65.7 versus IR = 78.0, ER = 82.7, p = 0.001) and role functioning (A = 67.5, IR-A = 52.8 versus IR = 79.2, ER = 80.6, p = 0.039), both EORTC QLQ-C30 scales. Also for the TESS, the scores were significantly lower for the amputation groups compared to the limb sparing groups (upper extremity p = 0.007 with A = 68.9, IR-A = 71.6 versus IR = 93.3, ER = 91.1; lower extremity p < 0.001 with A = 72.2, IR-A50.9 versus IR = 84.5 and ER = 85.5). There were no significant differences between the groups on cancer worry, anxiety and depression. Conclusion: HRQoL in eSTS survivors treated with IR or ER is equal; for maintenance of physical functioning and functionality IR and ER outperform an amputation

DNA Sequence Patterns – A Successful Example of Grid Computing in Genome Research and Building Virtual Super-Computers for the Research Commons of e-Societies

The amount of information is growing exponentially with ever-new technologies emerging and is believed to be always at the limit. In contrast, huge resources are obviously available, which are underused in the IT sector, similar as e.g. in the renewable energy sector. Genome research is one of the boosting areas, which needs an extreme amount of IT resources to analyse the sequential organization of genomes, i.e. the relations between distant base pairs and regions within sequences, and its connection to the three-dimensional organization of genomes, which is still a largely unresolved problem. The underusage of resources as those accessible by grid with its fast turnover rates is very astonishing considering the barriers for further development put forward by the inability to satisfy the need for such resources. The phenomenon is a typical example of the Inverse Tragedy of the Commons, i.e. resources are underexploited in contrast to the unsustainable and destructing overexploitation in the Classic Tragedy of the Commons. An analysis of IT and the grid sector which attempts to share resources for better usage efficiency, reveals two challenges, which lead to the heart of the paradox: i) From a macro perspective all grid infrastructures involve not only mere technical solutions but also dominantly all of the autopoietic social sub-systems ranging from religion to policy. ii) On the micro level the individual players and their psychology and risk behaviour are of major importance for acting within the macro autopoietic framework. Consequently, the challenges of grid implementation are similar to those of other pressing global issues as e.g. climate protection. This is well described by extending the Human Ecology triangle to a rectangle: invironment-individual-society-environment. By applying this extension of this classical field of interdisciplinary basic and applied research to the grid sector, i.e. by further extension to an e-Human Grid Ecology rational, the Grid Inverse Tragedy of the Commons can be understood and approached regarding the internalization challenge into e-Society and e-Life, from which then guidelines for the day-to-day management can be derived. This is of general importance for many complex fields and thus with similar paradoxes and challenges. By using grid Long-range power-law correlations were found using correlation analysis on almost the entire observable scale of 132 completely sequenced chromosomes of 0.5x106 to 3.0x107 bp from Archaea, Bacteria, Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens. The local correlation coeffi

Treatment dilemmas in patients with gastrointestinal stromal tumors (GIST) who experienced imatinib-induced pneumonitis:A case series

Introduction: Imatinib has led to a phenomenal progress in the treatment of GIST. A rare and lesser-known side effect of imatinib is pneumonitis, an uncommon multicausal interstitial lung disease. Methods: Patients registered within the Dutch GIST Registry (DGR) were reviewed. For the patients identified with an imatinib-induced pneumonitis we reported the time on imatinib to develop pneumonitis, how the pneumonitis was diagnosed, graded and managed, and how the GIST treatment was managed. Cases: Of the 1934 patients registered in the DGR, 1161 patients received imatinib at some point, of which nine patients (0.8 %) were identified with an imatinib-induced pneumonitis. At time of the pneumonitis, patients received a daily imatinib dose of 200–400 mg for a mean duration of 486 days. One patient was able to continue imatinib in a lower dose, in the other eight patients imatinib was interrupted, and six of these patients started prednisolone treatment. After management of the imatinib-induced pneumonitis, four patients stopped imatinib permanently, two patients were rechallenged with imatinib, and two patients started treatment with second-line sunitinib. Conclusion: Imatinib-induced pneumonitis is a rare side effect, which may affect GIST management considerably. After the management of imatinib-induced pneumonitis, clinicians are left with difficult treatment dilemmas.</p