Dosimetric benefits and preclinical performance of steerable needles in HDR prostate brachytherapy.

Prostate cancer patients with an enlarged prostate and/or excessive pubic arch interference (PAI) are generally considered non-eligible for high-dose-rate (HDR) brachytherapy (BT). Steerable needles have been developed to make these patients eligible again. This study aims to validate the dosimetric impact and performance of steerable needles within the conventional clinical setting. HDR BT treatment plans were generated, needle implantations were performed in a prostate phantom, with prostate volume > 55 cm3 and excessive PAI of 10 mm, and pre- and post-implant dosimetry were compared considering the dosimetric constraints: prostate V100 > 95 % (13.50 Gy), urethra D0.1cm3 < 115 % (15.53 Gy) and rectum D1cm3 < 75 % (10.13 Gy). The inclusion of steerable needles resulted in a notable enhancement of the dose distribution and prostate V100 compared to treatment plans exclusively employing rigid needles to address PAI. Furthermore, the steerable needle plan demonstrated better agreement between pre- and post-implant dosimetry (prostate V100: 96.24 % vs. 93.74 %) compared to the rigid needle plans (79.13 % vs. 72.86 % and 87.70 % vs. 81.76 %), with no major changes in the clinical workflow and no changes in the clinical set-up. The steerable needle approach allows for more flexibility in needle positioning, ensuring a highly conformal dose distribution, and hence, HDR BT is a feasible treatment option again for prostate cancer patients with an enlarged prostate and/or excessive PAI.

Refraining from closed reduction of displaced distal radius fractures in the emergency department-in short: the RECORDED trial.

BACKGROUND: With roughly 45,000 adult patients each year, distal radius fractures are one of the most common fractures in the emergency department. Approximately 60% of all these fractures are displaced and require surgery. The current guidelines advise to perform closed reduction of these fractures awaiting surgery, as it may lead to post-reduction pain relief and release tension of the surrounding neurovascular structures. Recent studies have shown that successful reduction does not warrant conservative treatment, while patients find it painful or even traumatizing. The aim of this study is to determine whether closed reduction can be safely abandoned in these patients. METHODS: In this multicenter randomized clinical trial, we will randomize between closed reduction followed by plaster casting and only plaster casting. Patients aged 18 to 75 years, presenting at the emergency department with a displaced distal radial fracture and requiring surgery according to the attending surgeon, are eligible for inclusion. Primary outcome is pain assessed with daily VAS scores from the visit to the emergency department until surgery. Secondary outcomes are function assessed by PRWHE, length of stay at the emergency department, length of surgery, return to work, patient satisfaction, and complications. A total of 134 patients will be included in this study with follow-up of 1 year. DISCUSSION: If our study shows that patients who did not receive closed reduction experience no significant drawbacks, we might be able to reorganize the initial care for distal radial fractures in the emergency department. If surgery is warranted, the patient can be sent home with a plaster cast to await the call for admission, decreasing the time spend in the emergency room drastically. TRIAL REGISTRATION: This trial was registered on January 27, 2023.

MR-guided HDR prostate brachytherapy with teleoperated steerable needles.

Conformity of tumour volumes and dose plans in prostate brachytherapy (BT) can be constrained by unwanted needle deflections, needle access restrictions and visualisation limitations. This work validates the feasibility of teleoperated robotic control of an active steerable needle using magnetic resonance (MR) for guidance. With this system, perturbations can be counteracted and critical structures can be circumvented to access currently inaccessible areas. The system comprises of (1) a novel steerable needle, (2) the minimally invasive robotics in an MR environment (MIRIAM) system, and (3) the daVinci Research Kit (dVRK). MR scans provide visual feedback to the operator controlling the dVRK. Needle steering is performed along curved trajectories to avoid the urethra towards targets (representing tumour tissue) in a prostate phantom with a targeting error of 1.2 ± 1.0 mm. This work shows the potential clinical applicability of active needle steering for prostate BT with a teleoperated robotic system in an MR environment.

The relation between age and airway epithelial barrier function.

BACKGROUND: The prevalence of age-associated diseases, such as chronic obstructive pulmonary disease (COPD), is increasing as the average life expectancy increases around the world. We previously identified a gene signature for ageing in the human lung which included genes involved in apical and tight junction assembly, suggesting a role for airway epithelial barrier dysfunction with ageing. AIM: To investigate the association between genes involved in epithelial barrier function and age both in silico and in vitro in the airway epithelium. METHODS: We curated a gene signature of 274 genes for epithelial barrier function and tested the association with age in two independent cohorts of bronchial brushings from healthy individuals with no respiratory disease, using linear regression analysis (FDR < 0.05). Protein-protein interactions were identified using STRING©. The barrier function of primary bronchial epithelial cells at air-liquid interface and CRISPR-Cas9-induced knock-down of target genes in human bronchial 16HBE14o-cells was assessed using Trans epithelial resistance (TER) measurement and Electric cell-surface impedance sensing (ECIS) respectively. RESULTS: In bronchial brushings, we found 55 genes involved in barrier function to be significantly associated with age (FDR < 0.05). EPCAM was most significantly associated with increasing age and TRPV4 with decreasing age. Protein interaction analysis identified CDH1, that was negatively associated with higher age, as potential key regulator of age-related epithelial barrier function changes. In vitro, barrier function was lower in bronchial epithelial cells from subjects > 45 years of age and significantly reduced in CDH1-deficient 16HBE14o-cells. CONCLUSION: The significant association between genes involved in epithelial barrier function and age, supported by functional studies in vitro, suggest a role for epithelial barrier dysfunction in age-related airway disease.

Axially rigid steerable needle with compliant active tip control.

Steerable instruments allow for precise access to deeply-seated targets while sparing sensitive tissues and avoiding anatomical structures. In this study we present a novel omnidirectional steerable instrument for prostate high-dose-rate (HDR) brachytherapy (BT). The instrument utilizes a needle with internal compliant mechanism, which enables distal tip steering through proximal instrument bending while retaining high axial and flexural rigidity. Finite element analysis evaluated the design and the prototype was validated in experiments involving tissue simulants and ex-vivo bovine tissue. Ultrasound (US) images were used to provide visualization and shape-reconstruction of the instrument during the insertions. In the experiments lateral tip steering up to 20 mm was found. Manually controlled active needle tip steering in inhomogeneous tissue simulants and ex-vivo tissue resulted in mean targeting errors of 1.4 mm and 2 mm in 3D position, respectively. The experiments show that steering response of the instrument is history-independent. The results indicate that the endpoint accuracy of the steerable instrument is similar to that of the conventional rigid HDR BT needle while adding the ability to steer along curved paths. Due to the design of the steerable needle sufficient axial and flexural rigidity is preserved to enable puncturing and path control within various heterogeneous tissues. The developed instrument has the potential to overcome problems currently unavoidable with conventional instruments, such as pubic arch interference in HDR BT, without major changes to the clinical workflow.

Does circumferential casting prevent fracture redisplacement in reduced distal radius fractures? A retrospective multicentre study.

BACKGROUND: This study evaluates whether a circumferential cast compared to a plaster splint leads to less fracture redisplacement in reduced extra-articular distal radius fractures (DRFs). METHODS: This retrospective multicentre study was performed in four hospitals (two teaching hospitals and two academic hospitals). Adult patients with a displaced extra-articular DRF, treated with closed reduction, were included. Patients were included from a 5-year period (January 2012-January 2017). According to the hospital protocol, fractures were immobilized with a below elbow circumferential cast (CC) or a plaster splint (PS). The primary outcome concerned the difference in the occurrence of fracture redisplacement at one-week follow-up. RESULTS: A total of 500 patients were included in this study (PS n = 184, CC n = 316). At one-week follow-up, fracture redisplacement occurred in 52 patients (17%) treated with a CC compared to 53 patients (29%) treated with a PS. This difference was statistically significant (p = 0.001). CONCLUSION: This study suggests that treatment of reduced DRFs with a circumferential cast might cause less fracture redisplacement at 1-week follow-up compared to treatment with a plaster splint. Level of Evidence Level III, Retrospective study.

Dedicated holmium microsphere administration device for MRI-guided interstitial brain microbrachytherapy.

Microbrachytherapy with radioactive holmium-166 (166Ho) microspheres (MS) has the potential to be an effective treatment method for brain malignancies. Direct intratumoural delivery of 166Ho-MS and dose coverage of the whole tumour are crucial requirements. However, currently no dedicated instruments for controlled intratumoural delivery exist. This study presents an administration device that facilitates this novel magnetic resonance imaging (MRI) -guided intervention. The bioceramic alumina oxide cannula creates a straight channel for a superelastic nitinol precurved stylet to control spatial deposition of Ho-MS. End-point accuracy of the stylet was measured during insertions in phantoms. Imaging tests were performed in a 3 Tesla MRI-scanner to quantify instrument-induced artefacts. Additionally, the feasibility of non-radioactive holmium-165 (165Ho)-MS delivery with the administration device was evaluated in a brain tumour simulant. Absolute stylet tip error was 0.88 ± 0.61 mm, instrument distortion in MRI depended on needle material and orientation and dose delivery of 165Ho-MS in a brain tumour phantom was possible. This study shows that the administration device can accurately place the stylet for injection of Ho-MS and that visualization can be performed with MRI.

Dedicated MRI staging versus surgical staging of peritoneal metastases in colorectal cancer patients considered for CRS-HIPEC; the DISCO randomized multicenter trial.

BACKGROUND: Selecting patients with peritoneal metastases from colorectal cancer (CRCPM) who might benefit from cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is challenging. Computed tomography generally underestimates the peritoneal tumor load. Diagnostic laparoscopy is often used to determine whether patients are amenable for surgery. Magnetic resonance imaging (MRI) has shown to be accurate in predicting completeness of CRS. The aim of this study is to determine whether MRI can effectively reduce the need for surgical staging. METHODS: The study is designed as a multicenter randomized controlled trial (RCT) of colorectal cancer patients who are deemed eligible for CRS-HIPEC after conventional CT staging. Patients are randomly assigned to either MRI based staging (arm A) or to standard surgical staging with or without laparoscopy (arm B). In arm A, MRI assessment will determine whether patients are eligible for CRS-HIPEC. In borderline cases, an additional diagnostic laparoscopy is advised. The primary outcome is the number of unnecessary surgical procedures in both arms defined as: all surgeries in patients with definitely inoperable disease (PCI > 24) or explorative surgeries in patients with limited disease (PCI < 15). Secondary outcomes include correlations between surgical findings and MRI findings, cost-effectiveness, and quality of life (QOL) analysis. CONCLUSION: This randomized trial determines whether MRI can effectively replace surgical staging in patients with CRCPM considered for CRS-HIPEC. TRIAL REGISTRATION: Registered in the clinical trials registry of U.S. National Library of Medicine under NCT04231175 .

The clinical relevance of indeterminate lung nodules in patients with locally recurrent rectal cancer.

AIM: To evaluate the clinical relevance of indeterminate lung nodules (ILN) in patients with locally recurrent rectal cancer (LRRC) treated in a tertiary referral centre. METHODS: All patients with LRRC diagnosed between 2000 and 2017 were retrospectively reviewed. Reports of staging chest CT-scans were evaluated for ILN. Patients with distant metastases including lung metastases at time of LRRC diagnosis were excluded. Overall (OS), progression-free survival (PFS) and the cumulative incidence of lung metastases were compared between patients with and without ILN. RESULTS: In total 556 patients with LRRC were treated during the study period. In the 243 patients eligible for analysis, 68 (28%) had ILN at LRRC diagnosis. Median OS was 37 months for both the patients with and without ILN (p = 0.37). Median PFS was 14 months for the patients with ILN and 16 months for patients without ILN (p = 0.80). After correction for potential confounding, ILN present at LRRC diagnosis was not associated with impaired OS or PFS (adjusted hazards ratio [95% confidence interval]: 0.81 [0.54-1.22] and 1.09 [0.75-1.59]). The 5-year cumulative incidence of lung metastases was 31% in patients with ILN and 28% in patients without ILN (p = 0.19). CONCLUSION: Our study shows that ILN are present in roughly a quarter of patients with LRRC. No differences in OS, PFS, or the cumulative incidence of lung metastases were found between patients with and without ILN at LRRC diagnosis. These results suggest that ILN are of little to no clinical relevance in patients with LRRC.

Identification of IgG1 isotype phosphorylcholine antibodies for the treatment of inflammatory cardiovascular diseases.

BACKGROUND: Phosphorylcholine (PC) is an important pro-inflammatory damage-associated molecular pattern. Previous data have shown that natural IgM anti-PC protects against cardiovascular disease. We aimed to develop a monoclonal PC IgG antibody with anti-inflammatory and anti-atherosclerotic properties. METHODS: Using various techniques PC antibodies were validated and optimized. In vivo testing was performed in a femoral artery cuff model in ApoE3*Leiden mice. Safety studies are performed in rats and cynomolgus monkeys. RESULTS: A chimeric anti-PC (PC-mAb(T15), consisting of a human IgG1 Fc and a mouse T15/E06 Fab) was produced, and this was shown to bind specifically to epitopes in human atherosclerotic tissues. The cuff model results in rapid induction of inflammatory genes and altered expression of genes associated with ER stress and choline metabolism in the lesions. Treatment with PC-mAb(T15) reduced accelerated atherosclerosis via reduced expression of endoplasmic reticulum stress markers and CCL2 production. Recombinant anti-PC Fab fragments were identified by phage display and cloned into fully human IgG1 backbones creating a human monoclonal IgG1 anti-PC (PC-mAbs) that specifically bind PC, apoptotic cells and oxLDL. Based on preventing macrophage oxLDL uptake and CCL2 production, four monoclonal PC-mAbs were selected, which to various extent reduced vascular inflammation and lesion development. Additional optimization and validation of two PC-mAb antibodies resulted in selection of PC-mAb X19-A05, which inhibited accelerated atherosclerosis. Clinical grade production of this antibody (ATH3G10) significantly attenuated vascular inflammation and accelerated atherosclerosis and was tolerated in safety studies in rats and cynomolgus monkeys. CONCLUSIONS: Chimeric anti-PCs can prevent accelerated atherosclerosis by inhibiting vascular inflammation directly and through reduced macrophage oxLDL uptake resulting in decreased lesions. PC-mAb represents a novel strategy for cardiovascular disease prevention.

Long-term follow-up of distal radius fractures, an evaluation of the current guideline: the relation between malunion, osteoarthritis and functional outcome.

BACKGROUND: Last decades there is an increased tendency of performing surgery on displaced distal radius fractures. However, it is unclear whether this affects the development of osteoarthritis. This study aims to determine the relation between anatomical position, radiological osteoarthritis and functional outcome of the elderly wrist, 10-15 years after a distal radius fracture. PATIENTS AND METHODS: 173 patients between the age of 50 and 70 at time of trauma were included in this retrospective cohort study with a 10-15-year follow-up. Based on the reassessed initial X-rays, the patients were placed into 4 groups (1: anatomical, 2a: acceptable, 2b: current operative indication but treated conservative, 2c: operative indication and operated). Functional outcome was measured, questionnaires were answered, and new bilateral X-rays of the wrist were obtained. Factors influencing osteoarthritis, the difference in osteoarthritis between the groups and the difference between the fractured and non-fractured wrists were studied. RESULTS: Group 2b showed a significantly higher degree of osteoarthritis in comparison with the contralateral wrist. In the other groups, this difference was not observed. We found no significant difference in OA and functional outcomes between the groups. The degree of osteoarthritis of the non-fractured wrist appeared to be highly associated with osteoarthritis of the fractured wrist. CONCLUSION: The results of this study showed that the degree of radiocarpal osteoarthritis is higher in conservatively treated patients that should have been operated on according to current guidelines in comparison with patients without an indication for surgery. This might suggest that our current guidelines can be effective in prevention of posttraumatic osteoarthritis. However, the effect on the functional outcome is very limited. Since the degree of radiocarpal osteoarthritis of the non-fractured wrist appeared to be highly associated with the degree of osteoarthritis of the fractured wrist, future studies should always assess osteoarthritis of both wrists in order to study the real posttraumatic effect of a fracture.

Early diagnosis of ataxia telangiectasia in the neonatal phase: a parents' perspective.

Ataxia telangiectasia (A-T) is a severe neurodegenerative disorder with variable immunodeficiency. Together with the Dutch A-T community, we investigated the opinion of A-T parents on an early A-T diagnosis in the asymptomatic phase of the disease. During an annual national meeting for A-T patients and families, the topic of an early A-T diagnosis was discussed in relation to the recent introduction of neonatal screening for severe combined immunodeficiency (SCID) in the Netherlands. Based on the discussion, individual arguments were identified and processed into a questionnaire, which was sent out to 64 A-T parents (32 families). Arguments included were insecurity to diagnosis, possible medical advantages, appropriate genetic counseling and family planning, loss of "golden" year(s), and early cancer screening for parents. The response rate was 55% (n = 35 parents). Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.Conclusion: The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives. In addition, the knowledge of being carriers of an ATM gene mutation influenced decisions about family planning. Parents who opposed against an early diagnosis emphasized the joy of having a seemingly healthy child until diagnosis.What is Known:• Ataxia telangiectasia (A-T) is a devastating DNA repair disorder with a huge impact on quality of life of patients and their parents.• Patients with A-T may incidentally be identified at birth as the consequence of neonatal screening for severe combined immunodeficiency (SCID).What is New:• The majority of Dutch parents of A-T patients (74%) would have preferred an early diagnosis of their child in the asymptomatic phase of the disease.• Major arguments for an early A-T diagnosis were (1) the experienced insecurity in diagnostic trajectories and its impact on families and (2) the knowledge of being ATM mutation carriers when deciding about family planning. An argument against an early diagnosis is losing the joy of having a seemingly healthy child until diagnosis.

Omitting Postoperative Wound Drainage After Mastectomy With Skin-Flap Quilting.

BACKGROUND: Seroma is the most frequent complication after mastectomy (ME) and axillary lymph node dissection (ALND). The quilting suture technique, in which skin flaps are sutured to the underlying muscle, was previously investigated and found to reduce seroma incidence after ME and ALND. This study aimed to investigate whether postoperative wound drainage can safely be omitted when quilting sutures are applied. METHODS: Two groups with a total of 251 consecutive patients who underwent ME, ALND, or both were retrospectively compared. The first group underwent quilting sutures with wound vacuum drainage, and the second group underwent quilting sutures without wound drainage. The primary outcome was the incidence of postoperative clinically significant seroma (CSS). The secondary outcomes were the incidence of postoperative infection, bleeding complications, wound dehiscence, and flap necrosis. RESULTS: The group without a postoperative drain (n = 166) had a significantly lower CSS incidence (8.4%) than the group with a postoperative drain (n = 85, 21.2%) (p < 0.05). In the multivariate analysis, no significant predictors were found for seroma formation. Wound complications significantly decreased, from 31.8% in the group with a drain group to 17.5% in the group without a drain (p < 0.05). CONCLUSION: This study showed that the postoperative drain can be omitted when quilting sutures are applied in ME, ALND, or both. This facilitates day care mastectomy, eliminating drain-related care, discomfort, and related expenses.

Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels.

BACKGROUND: Plaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a natural occurring process to fulfil the increasing demand of oxygen and nourishment of the vessel wall. However, inadequate formed, immature plaque neovessels are leaky and cause intraplaque haemorrhage. OBJECTIVE: Blockade of VEGFR2 normalizes the unbridled process of plaque neovessel formation and induces maturation of nascent vessels resulting in prevention of intraplaque haemorrhage and influx of inflammatory cells into the plaque and subsequently increases plaque stability. METHODS AND RESULTS: In human carotid and vein graft atherosclerotic lesions, leaky plaque neovessels and intraplaque haemorrhage co-localize with VEGF/VEGFR2 and angiopoietins. Using hypercholesterolaemic ApoE3*Leiden mice that received a donor caval vein interposition in the carotid artery, we demonstrate that atherosclerotic vein graft lesions at t28 are associated with hypoxia, Hif1α and Sdf1 up-regulation. Local VEGF administration results in increased plaque angiogenesis. VEGFR2 blockade in this model results in a significant 44% decrease in intraplaque haemorrhage and 80% less extravasated erythrocytes compared to controls. VEGFR2 blockade in vivo results in a 32% of reduction in vein graft size and more stable lesions with significantly reduced macrophage content (30%), and increased collagen (54%) and smooth muscle cell content (123%). Significant decreased VEGF, angiopoietin-2 and increased Connexin 40 expression levels demonstrate increased plaque neovessel maturation in the vein grafts. VEGFR2 blockade in an aortic ring assay showed increased pericyte coverage of the capillary sprouts. CONCLUSION: Inhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.

The protective role of Toll-like receptor 3 and type-I interferons in the pathophysiology of vein graft disease.

BACKGROUND: Venous grafts are commonly used as conduits to bypass occluded arteries. Unfortunately, patency rates are limited by vein graft disease (VGD). Toll like receptors (TLRs) can be activated in vein grafts by endogenous ligands. This study aims to investigate the role of TLR3 in VGD. METHODS: Vein graft surgery was performed by donor caval vein interpositioning in the carotid artery of recipient Tlr2-/-, Tlr3-/-, Tlr4-/- and control mice. Vein grafts were harvested 7, 14 and 28d after surgery to perform immunohistochemical analysis. Expression of TLR-responsive genes in vein grafts was analysed using a RT2-profiler PCR Array. mRNA expression of type-I IFN inducible genes was measured with qPCR in bone marrow-derived macrophages (BMM). RESULTS: TLR2, TLR3 and TLR4 were observed on vein graft endothelial cells, smooth muscle cells and macrophages. Tlr3-/- vein grafts demonstrated no differences in vessel wall thickening after 7d, but after 14d a 2.0-fold increase (p = 0.02) and 28d a 1.8-fold increase (p = 0.009) compared to control vein grafts was observed, with an increased number of macrophages (p = 0.002) in the vein graft. Vessel wall thickening in Tlr4-/- decreased 0.6-fold (p = 0.04) and showed no differences in Tlr2-/- compared to control vein grafts. RT2-profiler array revealed a down-regulation of type-I IFN inducible genes in Tlr3-/- vein grafts. PolyI:C stimulated BMM of Tlr3-/- mice showed a reduction of Ifit1 (p = 0.003) and Mx1 (p < 0.0001) mRNA compared to control. CONCLUSIONS: We here demonstrate that TLR3 can play a protective role in VGD development, possibly regulated via type-I IFNs and a reduced inflammatory response.

The role of CD27-CD70-mediated T cell co-stimulation in vasculogenesis, arteriogenesis and angiogenesis.

BACKGROUND: T cells have a distinctive role in neovascularization, which consists of arteriogenesis and angiogenesis under pathological conditions and vasculogenesis under physiological conditions. However, the role of co-stimulation in T cell activation in neovascularization has yet to be established. The aim of this study was to investigate the role T cell co-stimulation and inhibition in angiogenesis, arteriogenesis and vasculogenesis. METHODS AND RESULTS: Hind limb ischemia was induced by double ligation of the left femoral artery in mice and blood flow recovery was measured with Laser Doppler Perfusion Imaging in control, CD70-/-, CD80/86-/-, CD70/80/86-/- and CTLA4+/- mice. Blood flow recovery was significantly impaired in mice lacking CD70 compared to control mice, but was similar in CD80/86-/-, CTLA4+/- and control mice. Mice lacking CD70 showed impaired vasculogenesis, since the number of pre-existing collaterals was reduced as observed in the pia mater compared to control mice. In vitro an impaired capability of vascular smooth muscle cells (VSMC) to activate T cells was observed in VSMC lacking CD70. Furthermore, CD70-/-, CD80/86-/- and CD70/80/86-/- mice showed reduced angiogenesis in the soleus muscle 10 days after ligation. Arteriogenesis was also decreased in CD70-/- compared to control mice 10 and 28 days after surgery. CONCLUSIONS: The present study is the first to describe an important role for T cell activation via co-stimulation in angiogenesis, arteriogenesis and vasculogenesis, where the CD27-CD70 T cell co-stimulation pathway appears to be the most important co-stimulation pathway in pre-existing collateral formation and post-ischemic blood flow recovery, by arteriogenesis and angiogenesis.

The association between the behavior rating inventory of executive functioning and cognitive testing in children diagnosed with a brain tumor.

Pediatric brain tumor survivors (PBTS) suffer from cognitive late effects, such as deteriorating executive functioning (EF). We explored the suitability of the Behavior Rating Inventory of Executive Function (BRIEF) to screen for these late effects. We assessed the relationship between the BRIEF and EF tasks, and between the BRIEF-Parent and BRIEF-Teacher, and we explored the clinical utility. Eighty-two PBTS (8-18 years) were assessed with EF tasks measuring attention, cognitive flexibility, inhibition, visual-, and working memory (WM), and with the BRIEF-Parent and BRIEF-Teacher. Pearson's correlations between the BRIEF and EF tasks, and between the BRIEF-Parent and BRIEF-Teacher were calculated. The BRIEF-Parent related poorly to EF tasks (rs < .26, ps > .01), but of the BRIEF-Teacher the WM-scale, Monitor-scale, Behavioral-Regulation-Index, and Meta-cognition-Index, and Total-score (rs > .31, ps < .01) related significantly to some EF tasks. When controlling for age, only the WM scale and Total score related significantly to the attention task (ps < .01). The inhibit scales of the BRIEF-Parent and BRIEF-Teacher correlated significantly (r = .33, p < .01). Children with clinically elevated scores on BRIEF scales that correlated with EF tasks performed worse on all EF tasks (ds 0.56-1.23, ps < .05). The BRIEF-Teacher Total and Index scores might better screen general EF in PBTS than the BRIEF-Parent. However, the BRIEF-Teacher is also not specific enough to capture separate EFs. Solely relying on the BRIEF as a screening measure of EFs in BPTS is insufficient. Questionnaires and tasks give distinctive, valuable information.

A protective role of IRF3 and IRF7 signalling downstream TLRs in the development of vein graft disease via type I interferons.

BACKGROUND: Toll like receptors (TLR) play an important role in vein graft disease (VGD). Interferon regulatory factors (IRF) 3 and 7 are the transcriptional regulators of type I interferons (IFN) and type I IFN responsive genes and are downstream factors of TLRs. Relatively little is known with regard to the interplay of IRFs and TLRs in VGD development. The aim of this study was to investigate the role of IRF3 and IRF7 signaling downstream TLRs and the effect of IRF3 and IRF7 in VGD. METHODS AND RESULTS: In vitro activation of TLR3 induced IRF3 and IRF7 dependent IFNß expression in bone marrow macrophages and vascular smooth muscle cells. Activation of TLR4 showed to regulate pro-inflammatory cytokines via IRF3. Vein graft surgery was performed in Irf3-/- , Irf7-/- and control mice. After 14 days Irf3-/- vein grafts had an increased vessel wall thickness compared to both control (P = 0.01) and Irf7-/- (P = 0.02) vein grafts. After 28 days, vessel wall thickness increased in Irf3-/- (P = 0.0003) and Irf7-/- (P = 0.04) compared to control vein grafts and also increased in Irf7-/- compared to Irf3-/- vein grafts (P = 0.02). Immunohistochemical analysis showed a significant higher influx of macrophages after 14 days in Irf3-/- vein grafts and after 28 days in Irf7-/- vein grafts compared to control vein grafts. CONCLUSIONS: The present study is the first to describe a protective role of both IRF3 and IRF7 in VGD. IRFs regulate VGD downstream TLRs since Irf3-/- and Irf7-/- vein grafts show increased vessel wall thickening after respectively 14 and 28 days after surgery.

Grainyhead-like Transcription Factors in Craniofacial Development.

Craniofacial development in vertebrates involves the coordinated growth, migration, and fusion of several facial prominences during embryogenesis, processes governed by strict genetic and molecular controls. A failure in any of the precise spatiotemporal sequences of events leading to prominence fusion often leads to anomalous facial, skull, and jaw formation-conditions termed craniofacial defects (CFDs). Affecting approximately 0.1% to 0.3% of live births, CFDs are a highly heterogeneous class of developmental anomalies, which are often underpinned by genetic mutations. Therefore, identifying novel disease-causing mutations in genes that regulate craniofacial development is a critical prerequisite to develop new preventive or therapeutic measures. The Grainyhead-like ( GRHL) transcription factors are one such gene family, performing evolutionarily conserved roles in craniofacial patterning. The antecedent member of this family, Drosophila grainyhead ( grh), is required for head skeleton development in fruit flies, loss or mutation of Grhl family members in mouse and zebrafish models leads to defects of both maxilla and mandible, and recently, mutations in human GRHL3 have been shown to cause or contribute to both syndromic (Van Der Woude syndrome) and nonsyndromic palatal clefts. In this review, we summarize the current knowledge regarding the craniofacial-specific function of the Grainyhead-like family in multiple model species, identify some of the major target genes regulated by the Grhl transcription factors in craniofacial patterning, and, by examining animal models, draw inferences as to how these data will inform the likely roles of GRHL factors in human CFDs comprising palatal clefting. By understanding the molecular networks regulated by Grhl2 and Grhl3 target genes in other systems, we can propose likely pathways that mediate the effects of these transcription factors in human palatogenesis.

[Emergency laparotomy in a trauma patient]. / De spoedlaparotomie bij een traumapatiënt.

- Emergency laparotomy in trauma patients can be part of the resuscitation process, is based on damage control principles and is therefore fundamentally different from elective laparotomy, for example in case of malignancies. - Indications for emergency laparotomy after trauma are based on haemodynamic instability of the patient and the procedure is focused on restoring the patient's physiological condition.- Haemodynamic and biochemical parameters are used to determine the rest of the strategy. In order to optimize the procedure, the entire treatment team should be practiced in this.- Fewer and fewer surgeons are carrying out general laparotomies and even fewer are carrying out emergency laparotomies after trauma.- Knowledge and skills about emergency laparotomy after trauma are at risk of disappearing because of this, not only for surgeons but also for other team members.- Increased centralisation, team training, more cooperation and consultation for specific indications may all contribute to expertise preservation.