Histone variant innovation in a rapidly evolving chordate lineage

Contains fulltext : 91896.pdf (publisher's version ) (Open Access

Fluorescence Lifetime Imaging Microcopy of Extravasating Cancer Cells in the Mouse Microenvironment

Objective. To determine (i) whether early viral kinetics or other markers during a modified treatment regimen are predictors of treatment outcome and (ii) whether fast responders can be treated for 24 weeks, without compromising the sustained virologic response (SVR) rate. Material and methods. One hundred "difficult-to-treat'' chronic hepatitis C patients (46 previous non-responders/relapsers (any genotype), 54 treatment-naive patients genotypes 1 and 4) were treated with triple antiviral induction therapy: amantadine hydrochloride and ribavirin, combined with 6 weeks interferon alfa-2b induction (weeks 1-2: 18 MU/day, weeks 3-4: 9 MU/day, weeks 5-6: 6 MU/day), thereafter combined with weekly peginterferon alfa-2b. Fast responders (>= 3 log(10) HCV RNA decline at week 4) were randomized to 24 or 48 weeks. Slow responders (= or = 5 IU/mL at week 16 became non-SVR. In previous non-responders/relapsers, the predictive value for SVR was 83% if HCV RNA was = 5 IU/mL at week 8 became non-SVR. Conclusions. With high-dose interferon induction, SVR and non-SVR can be predicted reliably within 16 weeks. Fast responders can be treated for 24 weeks, and SVR is independent of baseline viral load in fast responders

Chronic exposure of gingival fibroblasts to TLR2 or TLR4 agonist inhibits osteoclastogenesis but does not affect osteogenesis

Chronic exposure to periodontopathogenic bacteria such as Porphyromonas gingivalis and the products of these bacteria that interact with the cells of the tooth surrounding tissues can ultimately result in periodontitis. This is a disease that is characterized by inflammation-related alveolar bone degradation by the bone-resorbing cells, the osteoclasts. Interactions of bacterial products with Toll-like receptors (TLRs), in particular TLR2 and TLR4, play a significant role in this chronic inflammatory reaction, which possibly affects osteoclastic activity and osteogenic capacity. Little is known about how chronic exposure to specific TLR activators affects these two antagonistic activities. Here, we studied the effect of TLR activation on gingival fibroblasts (GF), cells that are anatomically close to infiltrating bacterial products in the mouth. These were co-cultured with naive osteoclast precursor cells (i.e., monocytes), as part of the peripheral blood mononuclear cells (PBMCs). Activation of GF co-cultures (GF + PBMCs) with TLR2 or TLR4 agonists resulted in a weak reduction of the osteoclastogenic potential of these cultures, predominantly due to TLR2. Interestingly, chronic exposure, especially to TLR2 agonist, resulted in increased release of TNF-α at early time points. This effect, was reversed at later time points, thus suggesting an adaptation to chronic exposure. Monocyte cultures primed with M-CSF + RANKL, led to the formation of bone-resorbing osteoclasts, irrespective of being activated with TLR agonists. Late activation of these co-cultures with TLR2 and with TLR4 agonists led to a slight decrease in bone resorption. Activation of GF with TLR2 and TLR4 agonists did not affect the osteogenic capacity of the GF cells. In conclusion, chronic exposure leads to diverse reactions; inhibitory with naive osteoclast precursors, not effecting already formed (pre-)osteoclasts. We suggest that early encounter of naive monocytes with TLR agonists may result in differentiation toward the macrophage lineage, desirable for clearing bacterial products. Once (pre-)osteoclasts are formed, these cells may be relatively insensitive for direct TLR stimulation. Possibly, TLR activation of periodontal cells indirectly stimulates osteoclasts, by secreting osteoclastogenesis stimulating inflammatory cytokines

Laparoscopy to predict the result of primary cytoreductive surgery in advanced ovarian cancer patients (LapOvCa-trial): a multicentre randomized controlled study

Contains fulltext : 108486.pdf (publisher's version ) (Open Access)BACKGROUND: Standard treatment of advanced ovarian cancer is surgery and chemotherapy. The goal of surgery is to remove all macroscopic tumour, as the amount of residual tumour is the most important prognostic factor for survival. When removal off all tumour is considered not feasible, neoadjuvant chemotherapy (NACT) in combination with interval debulking surgery (IDS) is performed. Current methods of staging are not always accurate in predicting surgical outcome, since approximately 40% of patients will have more than 1 cm residual tumour after primary debulking surgery (PDS). In this study we aim to assess whether adding laparoscopy to the diagnostic work-up of patients suspected of advanced ovarian carcinoma may prevent unsuccessful primary debulking surgery for ovarian cancer. METHODS: Multicentre randomized controlled trial, including all gynaecologic oncologic centres in the Netherlands and their affiliated hospitals. Patients are eligible when they are planned for PDS after conventional staging. Participants are randomized between direct PDS or additional diagnostic laparoscopy. Depending on the result of laparoscopy patients are treated by PDS within three weeks, followed by six courses of platinum based chemotherapy or with NACT and IDS 3-4 weeks after three courses of chemotherapy, followed by another three courses of chemotherapy. Primary outcome measure is the proportion of PDS's leaving more than one centimetre tumour residual in each arm. In total 200 patients will be randomized. Data will be analysed according to intention to treat. DISCUSSION: Patients who have disease considered to be resectable to less than one centimetre should undergo PDS to improve prognosis. However, there is a need for better diagnostic procedures because the current number of debulking surgeries leaving more than one centimetre residual tumour is still high. Laparoscopy before starting treatment for ovarian cancer can be an additional diagnostic tool to predict the outcome of PDS. Despite the absence of strong evidence and despite the possible complications, laparoscopy is already implemented in many countries. We propose a randomized multicentre trial to provide evidence on the effectiveness of laparoscopy before primary surgery for advanced stage ovarian cancer patients. TRIAL REGISTRATION: Netherlands Trial Register number NTR2644

Collateral Circulation and Outcome in Atherosclerotic Versus Cardioembolic Cerebral Large Vessel Occlusion

Background and Purpose- Due to chronic hypoperfusion, cervical atherosclerosis may promote cerebral collateral circulation. We hypothesized that patients with ischemic stroke due to cervical carotid atherosclerosis have a more extensive collateral circulation and better outcomes than patients with cardioembolism. We tested this hypothesis in a population of patients who underwent endovascular treatment for large vessel occlusion. Methods- From the MR-CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), we selected consecutive adult endovascular treatment patients (March 2014 to June 2016) with acute ischemic stroke due to anterior circulation large vessel occlusion and compared patients with cervical carotid artery stenosis >50% to those with cardioembolic etiology. The primary outcome was collateral score, graded on a 4-point scale. Secondary outcomes included the modified Rankin Scale (mRS) score and mortality at 90 days. We performed multivariable regression analyses and adjusted for potential confounders. Results- Of 1627 patients in the Registry, 190 patients with cervical carotid atherosclerosis and 476 with cardioembolism were included. Patients with cervical carotid atherosclerosis were younger (median 69 versus 76 years, P<0.001), more often male (67% versus 47%, P<0.001), more often had an internal carotid artery terminus occlusion (33% versus 18%, P<0.001), and a lower prestroke mRS (mRS score, 0-2; 96% versus 85%, P<0.001), than patients with cardioembolism. Stroke due to cervical carotid atherosclerosis was associated with higher collateral score (adjusted common odds ratio, 1.67 [95% CI, 1.17-2.39]) and lower median mRS at 90 days (adjusted common odds ratio, 1.45 [95% CI, 1.03-2.05]) compared with cardioembolic stroke. There was no statistically significant difference in proportion of mRS 0-2 (aOR, 1.36 [95% CI, 0.90-2.07]) or mortality at 90 days (aOR, 0.80 [95% CI, 0.48-1.34]). Conclusions- Patients with stroke due to cervical carotid atherosclerosis had a more extensive cerebral collateral circulation and a slightly better median mRS at 90 days than patients with cardioembolic stroke

Clinical and Imaging Determinants of Collateral Status in Patients With Acute Ischemic Stroke in MR CLEAN Trial and Registry

Background and Purpose—Collateral circulation status at baseline is associated with functional outcome after ischemic stroke and effect of endovascular treatment. We aimed to identify clinical and imaging determinants that are associated with collateral grade on baseline computed tomography angiography in patients with acute ischemic stroke due to an anterior circulation large vessel occlusion. Methods—Patients included in the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; n=500) and MR CLEAN Registry (n=1488) were studied. Collateral status on baseline computed tomography angiography was scored from 0 (absent) to 3 (good). Multivariable ordinal logistic regression analyses were used to test the association of selected determinants with collateral status. Results—In total, 1988 patients were analyzed. Distribution of the collateral status was as follows: absent (7%, n=123), poor (32%, n=596), moderate (39%, n=735), and good (23%, n=422). Associations for a poor collateral status in a multivariable model existed for age (adjusted common odds ratio, 0.92 per 10 years [95% CI, 0.886–0.98]), male (adjusted common odds ratio, 0.64 [95% CI, 0.53–0.76]), blood glucose level (adjusted common odds ratio, 0.97 [95% CI, 0.95–1.00]), and occlusion of the intracranial segment of the internal carotid artery with occlusion of the terminus (adjusted common odds ratio 0.50 [95% CI, 0.41–0.61]). In contrast to previous studies, we did not find an association between cardiovascular risk factors and collateral status. Conclusions—Older age, male sex, high glucose levels, and intracranial internal carotid artery with occlusion of the terminus occlusions are associated with poor computed tomography angiography collateral grades in patients with acute ischemic stroke eligible for endovascular treatment

How can care settings for people with intellectual disabilities embed health promotion?

Background: People with intellectual disabilities (ID) depend on their environment to live healthily. Asset-based health promotion enhances a settings’ health-promoting capacity starting with identifying protective or promotive factors that sustain health. Method: This inclusive mixed-methods study used group sessions to generate and rank ideas on assets supporting healthy nutrition and physical activity in Dutch intellectual disability care settings. Participants included people with moderate intellectual disabilities and family and care professionals of people with severe/profound intellectual disabilities. Results: Fifty-one participants identified 185 assets in group sessions. They include the following: (i) the social network and ways “people” can support, (ii) assets in/around “places,” and person–environment fit, and (iii) “preconditions”: health care, prevention, budget, and policy. Conclusion: This inclusive research provides a user perspective on assets in the living environment supporting healthy living. This gives insight in contextual factors needed for development and sustainable embedment of health promotion in the systems of intellectual disability support settings

Influence of Onset to Imaging Time on Radiological Thrombus Characteristics in Acute Ischemic Stroke

Introduction: Radiological thrombus characteristics are associated with patient outcomes and treatment success after acute ischemic stroke. These characteristics could be expected to undergo time-dependent changes due to factors influencing thrombus architecture like blood stasis, clot contraction, and natural thrombolysis. We investigated whether stroke onset-to-imaging time was associated with thrombus length, perviousness, and density in the MR CLEAN Registry population.Methods: We included 245 patients with M1-segment occlusions and thin-slice baseline CT imaging from the MR CLEAN Registry, a nation-wide multicenter registry of patients who underwent endovascular treatment for acute ischemic stroke within 6.5 h of onset in the Netherlands. We used multivariable linear regression to investigate the effect of stroke onset-to-imaging time (per 5 min) on thrombus length (in mm), perviousness and density (both in Hounsfield Units). In the first model, we adjusted for age, sex, intravenous thrombolysis, antiplatelet use, and history of atrial fibrillation. In a second model, we additionally adjusted for observed vs. non-observed stroke onset, CT-angiography collateral score, direct presentation at a thrombectomy-capable center vs. transfer, and stroke etiology. We performed exploratory subgroup analyses for intravenous thrombolysis administration, observed vs. non-observed stroke onset, direct presentation vs. transfer, and stroke etiology.Results: Median stroke onset-to-imaging time was 83 (interquartile range 53–141) min. Onset to imaging time was not associated with thrombus length nor perviousness (β 0.002; 95% CI −0.004 to 0.007 and β −0.002; 95% CI −0.015 to 0.011 per 5 min, respectively) and was weakly associated with thrombus density in the fully adjusted model (adjusted β 0.100; 95% CI 0.005–0.196 HU per 5 min). The subgroup analyses showed no heterogeneity of these findings in any of the subgroups, except for a significantly positive relation between onset-to-imaging time and thrombus density in patients transferred from a primary stroke center (adjusted β 0.18; 95% CI 0.022–0.35).Conclusion: In our population of acute ischemic stroke patients, we found no clear association between onset-to-imaging time and radiological thrombus characteristics. This suggests that elapsed time from stroke onset plays a limited role in the interpretation of radiological thrombus characteristics and their effect on treatment results, at least in the early time window

Automatic segmentation of cerebral infarcts in follow-up computed tomography images with convolutional neural networks

Background and purpose: Infarct volume is a valuable outcome measure in treatment trials of acute ischemic stroke and is strongly associated with functional outcome. Its manual volumetric assessment is, however, too demanding to be implemented in clinical practice. Objective: To assess the value of convolutional neural networks (CNNs) in the automatic segmentation of infarct volume in follow-up CT images in a large population of patients with acute ischemic stroke. Materials and methods: We included CT images of 1026 patients from a large pooling of patients with acute ischemic stroke. A reference standard for the infarct segmentation was generated by manual delineation. We introduce three CNN models for the segmentation of subtle, intermediate, and severe hypodense lesions. The fully automated infarct segmentation was defined as the combination of the results of these three CNNs. The results of the three-CNNs approach were compared with the results from a single CNN approach and with the reference standard segmentations. Results: The median infarct volume was 48 mL (IQR 15–125 mL). Comparison between the volumes of the three-CNNs approach and manually delineated infarct volumes showed excellent agreement, with an intraclass correlation coefficient (ICC) of 0.88. Even better agreement was found for severe and intermediate hypodense infarcts, with ICCs of 0.98 and 0.93, respectively. Although the number of patients used for training in the single CNN approach was much larger, the accuracy of the three-CNNs approach strongly outperformed the single CNN approach, which had an ICC of 0.34. Conclusion: Convolutional neural networks are valuable and accurate in the quantitative assessment of infarct volumes, for both subtle and severe hypodense infarcts in follow-up CT images. Our proposed three-CNNs approach strongly outperforms a more straightforward single CNN approach

Automatic segmentation of cerebral infarcts in follow-up computed tomography images with convolutional neural networks

Background and purpose: Infarct volume is a valuable outcome measure in treatment trials of acute ischemic stroke and is strongly associated with functional outcome. Its manual volumetric assessment is, however, too demanding to be implemented in clinical practice. Objective: To assess the value of convolutional neural networks (CNNs) in the automatic segmentation of infarct volume in follow-up CT images in a large population of patients with acute ischemic stroke. Materials and methods: We included CT images of 1026 patients from a large pooling of patients with acute ischemic stroke. A reference standard for the infarct segmentation was generated by manual delineation. We introduce three CNN models for the segmentati