Force-field perturbations and muscle vibration strengthen stability-related foot placement responses during steady-state gait in healthy adults.

Mediolateral gait stability can be maintained by coordinating our foot placement with respect to the center-of-mass (CoM) kinematic state. Neurological impairments can reduce the degree of foot placement control. For individuals with such impairments, interventions that could improve foot placement control could thus contribute to improved gait stability. In this study we aimed to better understand two potential interventions, by investigating their effect in neurologically intact individuals. The degree of foot placement control can be quantified based on a foot placement model, in which the CoM position and velocity during swing predict subsequent foot placement. Previously, perturbing foot placement with a force-field resulted in an enhanced degree of foot placement control as an after-effect. Moreover, timed muscle vibration enhanced the degree of foot placement control whilst the vibration was applied. Here, we replicated these two findings and further investigated whether Q1) timed muscle vibration leads to an after-effect and Q2) whether combining timed muscle vibration with force-field perturbations leads to a larger after-effect, as compared to force-field perturbations only. In addition, we evaluated several potential contributors to the degree of foot placement control, by considering foot placement errors, CoM variability and the CoM position gain (ßpos) of the foot placement model, next to the R2 measure as the degree of foot placement control. Timed muscle vibration led to a higher degree of foot placement control as an after-effect (Q1). However, combining timed muscle vibration and force-field perturbations did not lead to a larger after-effect, as compared to following force-field perturbations only (Q2). Furthermore, we showed that the improved degree of foot placement control following force-field perturbations and during/following muscle vibration, did not reflect diminished foot placement errors. Rather, participants demonstrated a stronger active response (higher ßpos) as well as higher CoM variability.

BluePrint molecular subtypes predict response to neoadjuvant pertuzumab in HER2-positive breast cancer.

BACKGROUND: The introduction of pertuzumab has greatly improved pathological complete response (pCR) rates in HER2-positive breast cancer, yet effects on long-term survival have been limited and it is uncertain which patients derive most benefit. In this study, we determine the prognostic value of BluePrint subtyping in HER2-positive breast cancer. Additionally, we evaluate its use as a biomarker for predicting response to trastuzumab-containing neoadjuvant chemotherapy with or without pertuzumab. METHODS: From a cohort of patients with stage II-III HER2-positive breast cancer who were treated with neoadjuvant chemotherapy and trastuzumab with or without pertuzumab, 836 patients were selected for microarray gene expression analysis, followed by readout of BluePrint standard (HER2, Basal and Luminal) and dual subtypes (HER2-single, Basal-single, Luminal-single, HER2-Basal, Luminal-HER2, Luminal-HER2-Basal). The associations between subtypes and pathological complete response (pCR), overall survival (OS) and breast cancer-specific survival (BCSS) were assessed, and pertuzumab benefit was evaluated within the BluePrint subgroups. RESULTS: BluePrint results were available for 719 patients. In patients with HER2-type tumors, the pCR rate was 71.9% in patients who received pertuzumab versus 43.5% in patients who did not (adjusted Odds Ratio 3.43, 95% CI 2.36-4.96). Additionally, a significantly decreased hazard was observed for both OS (adjusted hazard ratio [aHR] 0.45, 95% CI 0.25-0.80) and BCSS (aHR 0.46, 95% CI 0.24-0.86) with pertuzumab treatment. Findings were similar in the HER2-single subgroup. No significant benefit of pertuzumab was seen in other subtypes. CONCLUSIONS: In patients with HER2-type or HER2-single-type tumors, pertuzumab significantly improved the pCR rate and decreased the risk of breast cancer mortality, which was not observed in other subtypes. BluePrint subtyping may be valuable in future studies to identify patients that are likely to be highly sensitive to HER2-targeting agents.

Differential effects of ankle constraints on foot placement control between normal and split belt treadmills.

Mediolateral ankle moment control contributes to gait stability. Ankle moments can be constrained by walking with a shoe with a ridge underneath the sole, narrowing the mediolateral support surface. In our previous study, such ankle moment constraints resulted in an increased step width and a decrease in the degree of foot placement control, as defined by the percentage of variance in foot placement that can be explained by CoM state. However, since our previous study was performed on a split-belt treadmill and the narrow ridge could fit inside the gap between the belts, it is not evident whether these effects can be attributed to the constrained ankle moment control or to avoidance of this gap. Therefore, we investigated if the effects of ankle moment constraints are dependent on whether participants walk on a normal treadmill or a split-belt treadmill. We included fourteen healthy young adults. Walking with constrained ankle moment control resulted in a wider step width on both treadmills. Yet, the increase in step width was larger on the split-belt treadmill compared to on the normal treadmill. We only found a decreased degree of foot placement control on the split-belt treadmill, whilst the degree of foot placement control increased on the normal treadmill. We conclude that the effects of ankle moment constraints reported in our previous study were confounded by the use of a split-belt treadmill. For future research, we recommend using a normal treadmill whenever possible, because the gap in a split-belt treadmill might affect gait parameters.

The effect of external lateral stabilization on ankle moment control during steady-state walking.

External lateral stabilization can help identify stability control mechanisms during steady-state walking. The degree of step-by-step foot placement control and step width are known to decrease when walking with external lateral stabilization. Here, we investigated the effect of external lateral stabilization on ankle moment control in healthy participants. Ankle moment control complements foot placement, by allowing a corrective center-of-pressure shift once the foot has been placed. This is reflected by a model predicting this center-of-pressure shift based on the preceding foot placement error. Here, the absolute explained variance accounted for by this model decreased when walking with external lateral stabilization. In other words, we found a reduction in the contribution of step-by-step ankle moment control to mediolateral gait stability when externally stabilized. Concurrently, foot placement error and the average center-of-pressure shift remained unchanged.

De-escalation of radiotherapy after primary chemotherapy in cT1-2N1 breast cancer (RAPCHEM; BOOG 2010-03): 5-year follow-up results of a Dutch, prospective, registry study.

BACKGROUND: Primary chemotherapy in breast cancer poses a dilemma with regard to adjuvant locoregional radiotherapy, as guidelines for locoregional radiotherapy were originally based on pathology results of primary surgery. We aimed to evaluate the oncological safety of de-escalated locoregional radiotherapy in patients with cT1-2N1 breast cancer treated with primary chemotherapy, according to a predefined, consensus-based study guideline. METHODS: In this prospective registry study (RAPCHEM, BOOG 2010-03), patients referred to one of 17 participating radiation oncology centres in the Netherlands between Jan 1, 2011, and Jan 1, 2015, with cT1-2N1 breast cancer (one to three suspicious nodes on imaging before primary chemotherapy, of which at least one had been pathologically confirmed), and who were treated with primary chemotherapy and surgery of the breast and axilla were included in the study. The study guideline comprised three risk groups for locoregional recurrence, with corresponding locoregional radiotherapy recommendations: no chest wall radiotherapy and no regional radiotherapy in the low-risk group, only local radiotherapy in the intermediate-risk group, and locoregional radiotherapy in the high-risk group. Radiotherapy consisted of a biologically equivalent dose of 25 fractions of 2 Gy, with or without a boost. During the study period, the generally applied radiotherapy technique in the Netherlands was forward-planned or inverse-planned intensity modulated radiotherapy. 5-year follow-up was assessed, taking into account adherence to the study guideline, with locoregional recurrence rate as primary endpoint. We hypothesised that 5-year locoregional recurrence rate would be less than 4% (upper-limit 95% CI 7·8%). This study was registered at ClinicalTrials.gov, NCT01279304, and is completed. FINDINGS: 838 patients were eligible for 5-year follow-up analyses: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 5-year locoregional recurrence rate in all patients was 2·2% (95% CI 1·4-3·4). The 5-year locoregional recurrence rate was 2·1% (0·9-4·3) in the low-risk group, 2·2% (1·0-4·1) in the intermediate-risk group, and 2·3% (0·8-5·5) in the high-risk group. If the study guideline was followed, the locoregional recurrence rate was 2·3% (0·8-5·3) for the low-risk group, 1·0% (0·2-3·4) for the intermediate-risk group, and 1·4% (0·3-4·5) for the high-risk group. INTERPRETATION: In this study, the 5-year locoregional recurrence rate was less than 4%, which supports our hypothesis that it is oncologically safe to de-escalate locoregional radiotherapy based on locoregional recurrence risk, in selected patients with cT1-2N1 breast cancer treated with primary chemotherapy, according to this predefined, consensus-based study guideline. FUNDING: Dutch Cancer Society. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Dynamic Contrast-enhanced and Diffusion-weighted Magnetic Resonance Imaging for Response Evaluation After Single-Dose Ablative Neoadjuvant Partial Breast Irradiation.

Purpose: We aimed to evaluate changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) scans acquired before and after single-dose ablative neoadjuvant partial breast irradiation (NA-PBI), and explore the relation between semiquantitative MRI parameters and radiologic and pathologic responses. Methods and Materials: We analyzed 3.0T DCE and DW-MRI of 36 patients with low-risk breast cancer who were treated with single-dose NA-PBI, followed by breast-conserving surgery 6 or 8 months later. MRI was acquired before NA-PBI and 1 week, 2, 4, and 6 months after NA-PBI. Breast radiologists assessed the radiologic response and breast pathologists scored the pathologic response after surgery. Patients were grouped as either pathologic responders or nonresponders (<10% vs ≥10% residual tumor cells). The semiquantitative MRI parameters evaluated were time to enhancement (TTE), 1-minute relative enhancement (RE1min), percentage of enhancing voxels (%EV), distribution of washout curve types, and apparent diffusion coefficient (ADC). Results: In general, the enhancement increased 1 week after NA-PBI (baseline vs 1 week median - TTE: 15s vs 10s; RE1min: 161% vs 197%; %EV: 47% vs 67%) and decreased from 2 months onward (6 months median - TTE: 25s; RE1min: 86%; %EV: 12%). Median ADC increased from 0.83 × 10-3 mm2/s at baseline to 1.28 × 10-3 mm2/s at 6 months. TTE, RE1min, and %EV showed the most potential to differentiate between radiologic responses, and TTE, RE1min, and ADC between pathologic responses. Conclusions: Semiquantitative analyses of DCE and DW-MRI showed changes in relative enhancement and ADC 1 week after NA-PBI, indicating acute inflammation, followed by changes indicating tumor regression from 2 to 6 months after radiation therapy. A relation between the MRI parameters and radiologic and pathologic responses could not be proven in this exploratory study.

Can foot placement during gait be trained? Adaptations in stability control when ankle moments are constrained.

Accurate coordination of mediolateral foot placement, relative to the center of mass kinematic state, is one of the mechanisms which ensures mediolateral stability during human walking. Previously, we found that shoes constraining ankle moments decreased the degree of foot placement control with respect to the center of mass kinematic state. As such, ankle moment constraints can be seen as a perturbation of foot placement. Direct mechanical perturbations of the swing leg trajectory can improve the degree of foot placement control as an after-effect. Here, we asked whether constrained ankle moments could have a similar effect. If confirmed, this would offer a simple training tool for individuals with impaired foot placement control. Participants walked in three conditions; normal (baseline) while wearing shoes constraining ankle moments (training) and normal again (after-effects). The degree of foot placement control was calculated as the percentage of variance in foot placement that could be predicted based on the center of mass kinematic state in the preceding swing phase. During training, the degree of foot placement control decreased initially compared to baseline, but it gradually improved over time. In the after-effect condition, it was higher than during baseline, yet not significantly so. During training, we observed increased step width, decreased stride time and reduced local dynamic stability. In conclusion, constraining ankle moment control deteriorates the degree of foot placement control. A non-significant trend towards an improved degree of foot placement control after prolonged exposure to constrained ankle moments, allows for speculation on a training potential.

Ankle muscles drive mediolateral center of pressure control to ensure stable steady state gait.

During steady-state walking, mediolateral gait stability can be maintained by controlling the center of pressure (CoP). The CoP modulates the moment of the ground reaction force, which brakes and reverses movement of the center of mass (CoM) towards the lateral border of the base of support. In addition to foot placement, ankle moments serve to control the CoP. We hypothesized that, during steady-state walking, single stance ankle moments establish a CoP shift to correct for errors in foot placement. We expected ankle muscle activity to be associated with this complementary CoP shift. During treadmill walking, full-body kinematics, ground reaction forces and electromyography were recorded in thirty healthy participants. We found a negative relationship between preceding foot placement error and CoP displacement during single stance; steps that were too medial were compensated for by a lateral CoP shift and vice versa, steps that were too lateral were compensated for by a medial CoP shift. Peroneus longus, soleus and tibialis anterior activity correlated with these CoP shifts. As such, we identified an (active) ankle strategy during steady-state walking. As expected, absolute explained CoP variance by foot placement error decreased when walking with shoes constraining ankle moments. Yet, contrary to our expectations that ankle moment control would compensate for constrained foot placement, the absolute explained CoP variance by foot placement error did not increase when foot placement was constrained. We argue that this lack of compensation reflects the interdependent nature of ankle moment and foot placement control. We suggest that single stance ankle moments do not only compensate for preceding foot placement errors, but also assist control of the subsequent foot placement. Foot placement and ankle moment control are 'caught' in a circular relationship, in which constraints imposed on one will also influence the other.

Tumor-Infiltrating Lymphocytes in Low-Risk Patients With Breast Cancer Treated With Single-Dose Preoperative Partial Breast Irradiation.

PURPOSE: Preoperative partial breast irradiation (PBI) has the potential to induce tumor regression. We evaluated the differences in the numbers of preirradiation tumor infiltrating lymphocytes (TILs) between responders and nonresponders after preoperative PBI in low-risk patients with breast cancer. Furthermore, we evaluated the change in number of TILs before and after irradiation. METHODS AND MATERIALS: In the prospective ABLATIVE study, low-risk patients with breast cancer underwent treatment with single-dose preoperative PBI (20 Gy) to the tumor and breast-conserving surgery after 6 or 8 months. In the preirradiation diagnostic biopsy and postirradiation resection specimen, numbers of TILs in 3 square regions of 450 × 450 µm were counted manually. TILs were visualized with CD3, CD4, and CD8 immunohistochemistry. Differences in numbers of preirradiation TILs between responders and nonresponders were tested using Mann-Whitney U test. Responders were defined as pathologic complete or near-complete response, and nonresponders were defined "as all other response." Changes in numbers of TILs after preoperative PBI was evaluated with the Wilcoxon signed rank test. RESULTS: Preirradiation tissue was available from 28 patients, postirradiation tissue from 29 patients, resulting in 22 pairs of preirradiation and postirradiation tissue. In these 35 patients, 15 had pathologic complete response (43%), 11 had a near-complete response (31%), 7 had a partial response (20%), and 2 had stable disease (6%). The median numbers of CD3+ TILs, CD4+ TILs, and CD8+ TILs in the preirradiation tumor tissue were 49 (interquartile range [IQR], 36-80), 45 (IQR, 28-57), and 19 (IQR, 8-35), respectively. The number of preirradiation TILs did not differ significantly between responders and nonresponders. The median numbers of CD3+ TILs, CD4+ TILs, and CD8+ TILs in postirradiation tumor tissue were 17 (IQR, 13-31), 26 (IQR, 16-35), and 7 (IQR, 5-11), respectively. CONCLUSIONS: After preoperative PBI in this limited cohort, the number of TILs in tumor tissue decreased. No differences in numbers of preirradiation TILs between responders and nonresponders were observed.

A single dose of doxycycline after an ixodes ricinus tick bite to prevent Lyme borreliosis: An open-label randomized controlled trial.

OBJECTIVES: A single dose of doxycycline after a tick bite can prevent the development of Lyme borreliosis in North America, but extrapolation to Europe is hampered by differences in Borrelia burgdorferi sensu lato genospecies and tick species. We assessed the efficacy of prophylaxis after a tick bite in Europe. METHODS: We conducted an open-label randomized controlled trial, administering a single dose of 200 mg doxycycline within 72 h after removing an attached tick from the skin, compared to no treatment. Potential participants ≥ 8 years of age who reported a recent tick bite online were invited for the study. After informed consent, they were randomly assigned to either the prophylaxis or the no-treatment group. Participants in the prophylaxis group were asked to visit their general practitioner to administer the antibiotics. All participants were followed up by online questionnaires. Our primary outcome was the development of physician-confirmed Lyme borreliosis in a modified-intention-to-treat analysis. This study is registered in the Netherlands Trial Register (NTR3953) and is closed. RESULTS: Between April 11, 2013, and June 10, 2015, 3538 potential participants were randomized, of whom 1689 were included in the modified-intention-to-treat analysis. 10 cases of Lyme borreliosis were reported out of 1041 participants (0.96%) in the prophylaxis group, and 19 cases out of 648 no-treatment participants (2.9%), resulting in a relative risk reduction of 67% (95% CI 31 - 84%), and a number-needed-to-treat of 51 (95% CI 29 - 180). No serious adverse events were reported. CONCLUSIONS: This primary care-based trial provides evidence that a single dose of doxycycline can prevent the development of Lyme borreliosis after an Ixodes ricinus tick bite.

Discrepancies in digital hematopathology diagnoses for consultation and expert panel analysis.

Digital pathology with whole-slide imaging (WSI) has a large potential to make the process of expert consultation and expert panel diagnosis more rapid and more efficient. However, comparison with the current methods is necessary for validation of the technique. In this study, we determined if digital assessment of whole-slide images of hematopathology specimens with a focus on the assessment of lymphoma can be used for consultation and panel diagnostics. Ninety-three histological specimens with a suspicion for lymphoma were assessed both with conventional microscopy and digital microscopy with a wash out period between assessments. A consensus diagnosis was based on full concordance between the pathologists or, in case of discordances, was reached at a joint session at a multi-headed microscope. In 81% of the cases, there was a full concordance between digital and light microscopical assessment for all three pathologists. Discordances between conventional microscopy and digital pathology were present in 3% of assessments. In comparison with the consensus diagnosis, discordant diagnoses were made in 5 cases with digital microscopy and in 3 cases with light microscopy. The reported level of confidence and need for additional investigations were similar between assessment by conventional and by digital microscopy. In conclusion, the performance of assessment by digital pathology is in general comparable with that of conventional light microscopy and pathologists feel confident using digital pathology for this subspecialty.

Active foot placement control ensures stable gait: Effect of constraints on foot placement and ankle moments.

Step-by-step foot placement control, relative to the center of mass (CoM) kinematic state, is generally considered a dominant mechanism for maintenance of gait stability. By adequate (mediolateral) positioning of the center of pressure with respect to the CoM, the ground reaction force generates a moment that prevents falling. In healthy individuals, foot placement is complemented mainly by ankle moment control ensuring stability. To evaluate possible compensatory relationships between step-by-step foot placement and complementary ankle moments, we investigated the degree of (active) foot placement control during steady-state walking, and under either foot placement-, or ankle moment constraints. Thirty healthy participants walked on a treadmill, while full-body kinematics, ground reaction forces and EMG activities were recorded. As a replication of earlier findings, we first showed step-by-step foot placement is associated with preceding CoM state and hip ab-/adductor activity during steady-state walking. Tight control of foot placement appears to be important at normal walking speed because there was a limited change in the degree of foot placement control despite the presence of a foot placement constraint. At slow speed, the degree of foot placement control decreased substantially, suggesting that tight control of foot placement is less essential when walking slowly. Step-by-step foot placement control was not tightened to compensate for constrained ankle moments. Instead compensation was achieved through increases in step width and stride frequency.

Radiotherapy after primary CHEMotherapy (RAPCHEM): Practice variation in a Dutch registration study (BOOG 2010-03).

BACKGROUND: We conducted a prospective cohort study in the Netherlands (RAPCHEM: NCT01279304, BOOG 2010-03) in breast cancer (BC) patients treated with primary systemic therapy (PST), followed by surgery and post-operative radiation therapy (RT) according to a predefined consensus-based study-guideline (SG). The aim of the current analysis is to evaluate adherence to the SG. METHODS: From January 2011 to January 2015, patients with cT1-2N1 BC treated in 17 Dutch RT Centres were included. Patients with four or more suspicious nodes at imaging were excluded. SG recommended whole breast RT for patients treated with breast conserving therapy. SG on loco(-regional) RT were defined for three risk groups based on the ypN status: (1) ypN0 (low-risk): RT breast and no RT after mastectomy; (2) ypN1 (intermediate-risk): RT breast or chest wall; (3) ypN2 (high-risk): RT breast or chest wall, including regional lymph nodes. RESULTS: We included 848 patients: 292 in the low-risk group; 374 in the intermediate-risk group; 182 in the high-risk group. Overall, 64% of the patients was treated according to the SG; 11% received less RT than the predefined target volumes and 25% received more extensive RT than according to the SG. The largest variation was seen in the intermediate risk group, where only 54% was treated according to the SG. CONCLUSION: Substantial deviation from the SG for post-operative RT was observed after PST, especially in patients with an intermediate-risk. Future analyses will evaluate outcome of these patients in relation to risk factors and the actual RT given.

Tumor Response After Neoadjuvant Magnetic Resonance Guided Single Ablative Dose Partial Breast Irradiation.

PURPOSE: To assess the pathologic and radiologic response in patients with low-risk breast cancer treated with magnetic resonance (MR) guided neoadjuvant partial breast irradiation (NA-PBI) and to evaluate toxicity and patient-reported outcomes (PROs). METHODS AND MATERIALS: For this single-arm prospective trial, women with unifocal, non-lobular tumors with a maximum diameter of 20 mm (age, 50-70 years) or 30 mm (age, ≥70 years) and tumor-negative sentinel node(s) were eligible. Patients were treated with a single ablative dose of NA-PBI followed by breast-conserving surgery after an interval of 6 to 8 months. Target volumes were defined on radiation therapy planning computed tomography scan and additional magnetic resonance imaging. Prescribed doses to gross tumor volume and clinical target volume (gross tumor volume plus 20 mm margin) were 20 Gy and 15 Gy, respectively. Primary outcome was pathologic complete response (pCR). Secondary outcomes were radiologic response (on magnetic resonance imaging), toxicity (Common Terminology Criteria for Adverse Events), PROs (European Organisation for Research and Treatment of Cancer QLQ-BR23, Hospital Anxiety and Depression Scale), and cosmesis (assessed by patient, radiation oncologist, and BCCT.core software). RESULTS: Thirty-six patients were treated with NA-PBI, and pCR was reported in 15 patients (42%; 95% confidence interval, 26%-59%). Radiologic complete response was observed in 15 patients, 10 of whom had pCR (positive predictive value, 67%; 95% confidence interval, 39%-87%). After a median follow-up of 21 months (range, 12-41), all patients experienced grade 1 fibrosis in the treated breast volume. Transient grade 2 and 3 toxicity was observed in 31% and 3% of patients, respectively. Local recurrences were absent. No deterioration in PROs or cosmetic results was observed. CONCLUSIONS: NA-PBI has the potential to induce pCR in a substantial proportion of patients, with acceptable toxicity. This treatment seems a feasible alternative to standard postoperative irradiation and could even result in postponement or omission of surgery if pCR can be accurately predicted in selected low-risk patients.

Postoperative microcirculatory perfusion and endothelial glycocalyx shedding following cardiac surgery with cardiopulmonary bypass.

We investigated microcirculatory perfusion disturbances following cardiopulmonary bypass in the early postoperative period and whether the course of these disturbances mirrored restoration of endothelial glycocalyx integrity. We performed sublingual sidestream dark field imaging of the microcirculation during the first three postoperative days in patients who had undergone on-pump coronary artery bypass graft surgery. We calculated the perfused vessel density, proportion of perfused vessels and perfused boundary region. Plasma was obtained to measure heparan sulphate and syndecan-1 levels as glycocalyx shedding markers. We recruited 17 patients; the mean (SD) duration of non-pulsatile cardiopulmonary bypass was 103 (18) min, following which 491 (29) ml autologous blood was transfused through cell salvage. Cardiopulmonary bypass immediately decreased both microcirculatory perfused vessel density; 11 (3) vs. 16 (4) mm.mm-2 , p = 0.052 and the proportion of perfused vessels; 92 (5) vs. 69 (9) %, p < 0.0001. The proportion of perfused vessels did not increase after transfusion of autologous salvaged blood following cardiopulmonary bypass; 72 (7) %, p = 0.19 or during the first three postoperative days; 71 (5) %, p < 0.0001. The perfused boundary region increased after cardiopulmonary bypass; 2.2 (0.3) vs. 1.9 (0.3) µm, p = 0.037 and during the first three postoperative days; 2.4 (0.3) vs. 1.9 (0.3) µm, p = 0.003. Increased plasma heparan sulphate levels were inversely associated with the proportion of perfused vessels during cardiopulmonary bypass; R = -0.49, p = 0.02. Plasma syndecan-1 levels were inversely associated with the proportion of perfused vessels during the entire study period; R = -0.51, p < 0.0001. Our study shows that cardiopulmonary bypass-induced acute microcirculatory perfusion disturbances persist in the first three postoperative days, and are associated with prolonged endothelial glycocalyx shedding. This suggests prolonged impairment and delayed recovery of both microcirculatory perfusion and function after on-pump cardiac surgery.

Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats.

BACKGROUND: Cardiopulmonary bypass (CPB) during cardiac surgery impairs microcirculatory perfusion and is paralleled by vascular leakage. The endothelial angiopoietin/Tie2 system controls microvascular leakage. This study investigated whether targeting Tie2 with the angiopoietin-1 mimetic vasculotide reduces vascular leakage and preserves microcirculatory perfusion in a rat CPB model. METHODS: Rats were subjected to 75 min of CPB after treatment with vasculotide or phosphate buffered solution as control or underwent a sham procedure. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n=10 per group) and Evans blue dye extravasation (n=13 per group), respectively. Angiopoietin-1, -2, and Tie2 protein and gene expression were determined in plasma, kidney, and lung. RESULTS: CPB immediately impaired microcirculatory perfusion [5 (4-8) vs 10 (7-12) vessels per recording, P=0.002] in untreated CPB rats compared with sham, which persisted after weaning from CPB. CPB increased circulating angiopoeietin-1, -2, and soluble Tie2 concentrations and reduced Tie2 messenger ribonucleic acid (mRNA) expression in kidney and lung. Moreover, CPB increased Evans blue dye leakage in kidney [12 (8-25) vs 7 (1-12) µg g-1, P=0.04] and lung [and 23 (13-60) vs 6 (4-16) µg g-1, P=0.001] compared with sham. Vasculotide treatment preserved microcirculatory perfusion during and after CPB. Moreover, vasculotide treatment reduced Evans blue dye extravasation in lung compared with CPB control [18 (6-28) µg g-1vs 23 (13-60) µg g-1, P=0.04], but not in kidney [10 (3-23) vs 12 (8-25) µg g-1, P=0.38]. Vasculotide did not affect circulating or mRNA expression of angiopoietin-1, -2, and Tie2 concentrations compared with untreated CPB controls. CONCLUSIONS: Treatment with the angiopoietin-1 mimetic vasculotide reduced pulmonary vascular leakage and preserved microcirculatory perfusion during CPB in a rat model.

Bilateral vanishing hips, coincidence or systemic disease? A case report and overview of current literature.

Rapidly progressive hip disease (RDHD) is a rare condition of the hip joint, causing destruction of the femoral head. The pathogenesis is unknown. The disease is self-limiting, there is no treatment to stop the disease. Hip arthroplasty is a successful way to relieve pain and restore function. We present a case where both hips were involved and analysed. A favourable result was obtained by bilateral total hip arthroplasty.

Are disseminated tumor cells in bone marrow and tumor-stroma ratio clinically applicable for patients undergoing surgical resection of primary colorectal cancer? The Leiden MRD study.

PURPOSE: Current TNM staging does not appropriately identify high-risk colorectal cancer (CRC) patients. The aim of this study was to evaluate whether the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) and the presence of stroma in the primary tumor, i.e., the tumor-stroma ratio (TSR), in patients undergoing surgical resection of primary CRC provides information relevant for disease outcome. METHODS: Patients with primary CRC (n = 125), consecutively admitted for curative resection between 2001 and 2007, were included in the study. All patients underwent BM aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC). The TSR was determined on diagnostic H&E stained sections of primary tumors. RESULTS: DTCs were detected in the BM of 23/125 patients (18 %). No association was found between BM status and overall survival (HR 0.97 (95 % CI 0.45-2.09), p = 0.93). Also, no significant difference was found in their 5-year survival rate (resp. 72 % and 68 % for BM-positive versus BM-negative patients). The TSR was found to be associated with a worse overall survival (HR 2.16, 95 % CI 1.02-4.57, p = 0.04) with 5-year survival rates of 84 % versus 62 % for stroma-low and stroma-high patients, respectively. No relation was found between the presence of DTCs and TSR. CONCLUSIONS: Our data indicate that the presence of DTCs in the BM of CRC patients is not associated with disease outcome. The TSR was, however, found to be associated with a worse overall survival, which indicates that for CRC the tumor microenvironment plays an important role in its behavior and prognosis.

Young male sex workers are at high risk for sexually transmitted infections, a cross-sectional study from Dutch STI clinics, the Netherlands, 2006-2012.

BACKGROUND: Male sex workers (MSW) are particularly exposed to sexually transmitted infections (STI) including HIV. In the Netherlands, data about STI among MSW are scarce. We estimated chlamydia, gonorrhoea, syphilis and HIV diagnoses among MSW attending STI clinics and determined associated factors to guide prevention policies. METHODS: Using 2006-2012 cross-sectional national surveillance data from Dutch STI clinics, we calculated the proportion of consultations with a positive test for any of three bacterial STI or HIV among MSW. Associated factors were determined by using Poisson logistic regression with robust variance. RESULTS: We identified 3,053 consultations involving MSW, of which 18.1 % included at least one positive bacterial STI test and 2.5 % a positive HIV test. Factors associated with bacterial STI and/or HIV diagnoses were respectively age groups < 35 y.o. and self-reporting homo- or bisexual preferences (aRR = 1.6; 95 % CI: 1.3-2.1), and age group 25-34 y.o. (aRR = 2.7; 95 % CI: 1.2-6.5) and self-reporting homo- or bisexual preferences (aRR = 24.4; 95 % CI: 3.4-176.9). Newly diagnosed and pre-existing HIV infection were associated with an increased risk for bacterial STI (aRR = 2.7, 95 % CI: 1.7-2.6 and aRR = 2.1, 95 % CI: 2.2-3.4 respectively). MSW with no history of HIV screening were more likely to be tested positive for HIV compared to those with a previous HIV-negative test (aRR = 2.6, 95 % CI: 1.6-4.3). CONCLUSION: Health promotion activities should target MSW who are young, homo- or bisexual, those who are HIV-infected or who have never been tested for HIV, to increase early diagnosis, prevention and treatment.