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Objective To discuss practical strategies to consider for morbidity and mortality conferences (M&M). Materials and Methods This article reflects on (i) insights that can be drawn from the M&M literature, (ii) practical aspects to consider when organizing M&M, and (iii) possible future directions for development for this long-standing practice for routine reflection. Results M&M offers the opportunity to learn from past cases in order to improve the care delivered to future patients, thereby serving both educational and quality improvement purposes. For departments seeking to implement or improve local M&M practice, it is difficult that a golden standard or best practice for M&M is nonexistent. This is partly because comparative research on different formats is hampered by the lack of objective outcome measures to evaluate the effectiveness of M&M. Common practical suggestions include the use of (i) a skillful and active moderator; (ii) structured formats for case presentation and discussion; and (iii) a dedicated committee to guide improvement plans that ensue from the meeting. M&M practice is affected by various sociological factors, for which qualitative research methods seem most suitable, but in the M&M literature these are sparsely used. Moreover, aspects influencing an open and blame-free atmosphere underline how local teams should tailor the format to best fit the local context and culture. Conclusion This article presents practice guidance on how to organize and carry out M&M This practice for routine reflection needs to be tailored to the local setting, with attention for various sociological factors that are at play. [ABSTRACT FROM AUTHOR]

Background Survival among dialysis patients with diabetes mellitus (DM) is inferior to survival of non-diabetic dialysis patients, probably due to the higher prevalence of diabetes-related comorbid conditions. One could hypothesize that these comorbid conditions also contribute to a decreased survival after amputation in diabetic patients compared with non-diabetic patients on dialysis. Methods Data were collected from the Netherlands Cooperative Study on the Adequacy of Dialysis, a multicentre, prospective cohort study in which new patients with end-stage renal disease were monitored until transplantation or death. Amputation rates (incident cases) were calculated in patients with and without DM. The primary endpoint was all-cause survival after first amputation during dialysis therapy in diabetic patients compared with non-diabetic dialysis patients with an amputation. This was formally assessed using interaction analysis (Poisson regression). Results During follow-up (mean duration 2.9 years), 50 of the 413 diabetic patients had a new amputation (12.1%), compared with 20 of 1553 non-diabetic patients (1.2%). Amputation rates/1000 person-years were 47.9 [95% confidence interval (CI) 36.3–63.2] and 4.1 (95% CI 2.7–6.4), respectively, for diabetic patients and non-diabetic patients. Amputation increased mortality risk more than 4-fold in patients without diabetes [hazard ratio (HR) 4.6 (95% CI 2.8–7.6)] as well as in patients with diabetes [HR 4.6 (95% CI 3.3–6.4)]. No formal interaction between diabetes and amputation was found (P = 0.12). Conclusions Amputation in dialysis patients is associated with a 4-fold increased mortality risk; this mortality risk was similar for diabetes and non-diabetes patients. Importantly, the risk for amputation is 10-fold higher in DM compared with non-diabetic dialysis patients. [ABSTRACT FROM AUTHOR]

Background: Central to Safety-II is promoting resilience of healthcare practices. In the "Room for Resilience" research project we focus on the role of horizontal and vertical accountability in healthcare teams and aim to discover how the relation between the two impacts team reflections and discussions. In this article, we report on an explorative study at the start of the project which aimed to assess the structures and dynamics of horizontal and vertical accountability. Methods: A qualitative study in six teams in three hospitals in the Netherlands. For the project, each team selected a specific clinical process to work on (e.g. pain assessment). We interviewed healthcare professionals, managers, and quality advisors about these processes, how they are discussed in practice and how teams need to account for them. Additionally, we observed the processes and how teams discuss them in practice. In total, we conducted 35 interviews and 67.5 h of observation. Transcripts and field notes were analyzed using thematic analysis. Results: Professionals at times varied in what they considered the right approach in the clinical process, with differing views on the importance of certain actions. When processes were discussed, this mostly was done during clinical work, and it often concerned reflections about the care for a specific patient instead of reflecting on the team's general approach of the clinical process. Organized reflections on the processes were sparse. How processes were conducted in practice deviated from guidelines, mainly due to staff shortages, a perceived lack of value of a guideline, equipment issues, and collaboration issues. For most processes, accountability to hierarchical layers consisted of quality indicator scores. Professionals were tasked with registering indicator data but did not find this meaningful for their work. Conclusions: The observed different perspectives within teams on what good quality care is show the importance of having team reflections about these processes. How vertical accountability was organized at times impacted the conditions for teams to discuss resilient performance. Following these findings, we recommend that reflection on resilient practice and the role of accountability processes is organized on all levels in (and outside) the organization. [ABSTRACT FROM AUTHOR]

Cell therapies involving the administration of bone marrow-derived mononuclear cells (BM-MNCs) for patients with chronic limb-threatening ischemia (CLTI) have shown promise; however, their overall effectiveness lacks evidence, and the exact mechanism of action remains unclear. In this study, we examined the angiogenic effects of well-controlled human bone marrow cell isolates on endothelial cells. The responses of endothelial cell proliferation, migration, tube formation, and aortic ring sprouting were analyzed in vitro, considering both the direct and paracrine effects of BM cell isolates. Furthermore, we conducted these investigations under both normoxic and hypoxic conditions to simulate the ischemic environment. Interestingly, no significant effect on the angiogenic response of human umbilical vein endothelial cells (HUVECs) following treatment with BM-MNCs was observed. This study fails to provide significant evidence for angiogenic effects from human bone marrow cell isolates on human endothelial cells. These in vitro experiments suggest that the potential benefits of BM-MNC therapy for CLTI patients may not involve endothelial cell angiogenesis. [ABSTRACT FROM AUTHOR]

Purpose: Perioperative risk assessments for complex aneurysms are based on the anatomical extent of the aneurysm and do not take the length of the aortic exclusion into account, as it was developed for open repair. Nevertheless, in the endovascular repair (ER) of complex aortic aneurysms, additional segments of healthy aorta are excluded compared with open repair (OR). The aim of this study was to assess differences in aortic exclusion between the ER and OR of complex aortic aneurysms, to subsequently assess the current classification for complex aneurysm repair. Methods: This retrospective observational study included patients that underwent complex endovascular aortic aneurysm repair by means of fenestrated endovascular aneurysm repair (FEVAR), fenestrated and branched EVAR (FBEVAR), or branched EVAR (BEVAR). The length of aortic exclusion and the number of patent segmental arteries were determined and compared per case in ER and hypothetical OR, using a Wilcoxon signed-rank test. Results: A total of 71 patients were included, who were treated with FEVAR (n = 44), FBEVAR (n = 8), or BEVAR (n = 19) for Crawford types I (n = 5), II (n = 7), III (n = 6), IV (n = 7), and V (n = 2) thoracoabdominal or juxtarenal (n = 44) aneurysms. There was a significant increase in the median exclusion of types I, II, III, IV, and juxtarenal aneurysms (p < 0.05) in ER, compared with hypothetical OR. The number of patent segmental arteries in the ER of type I–IV and juxtarenal aneurysms was significantly lower than in hypothetical OR (p < 0.05). Conclusion: There are significant differences in the length of aortic exclusion between ER and hypothetical OR, with the increased exclusion in ER resulting in a lower number of patent segmental arteries. The ER and OR of complex aortic aneurysms should be regarded as distinct modalities, and as each approach deserves a particular risk assessment, future efforts should focus on reporting on the extent of exclusion per treatment modality, to allow for appropriate comparison. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to investigate the effects of spaced versus massed practice on skill acquisition and retention in the context of laparoscopic motor skill training. Background: Reaching proficiency in performing laparoscopic surgery involves extensive training to acquire the required motor skills. Conventionally, training of such skills occurs during a full day training event utilizing surgical simulators that train specific motor skills pertinent to laparoscopic surgery. An important variable to consider is the optimal schedule for laparoscopic motor training. Methods: In this study, two groups of trainees without prior experience were trained on a variety of physical box-trainer tasks on different time-schedules. One group received three 75-min training sessions on a single day (massed condition) and the other received one 75-min training session per week for three consecutive weeks (spaced condition). Short- and long-term retention were assessed 2 weeks and 1 year after the completion of training. Results: Outcome measures indicated better performance at the end of training, at a 2-week delayed retention session and at a 1-year retention session for the group that received training on a spaced schedule. This spacing effect was most pronounced for the more difficult laparoscopic training tasks such as intra-corporeal suturing. On average, 21 % of participants in the massed group and 65 % in the spaced group reached proficiency by the end of training. Conclusions: Spacing practice of laparoscopic motor skill training will facilitate skill acquisition, short-term and long-term retention, and thus, a more efficient learning process for trainees. Though more challenging in terms of logistics, training courses in medical centers should distribute practice sessions over longer time intervals. [ABSTRACT FROM AUTHOR]

Background: In diagnosing peripheral arterial disease (PAD), medial arterial calcification (MAC) hampers arterial compression and could lead to unreliable ankle brachial index (ABI), toe brachial index (TBI) and toe pressure (TP). Doppler ultrasonography (DUS) derived maximal systolic acceleration (ACCmax) might be more accurate to diagnose PAD. In an in vitro study, a strong correlation between ACCmax and the severity of stenotic disease was determined. The aim of this study was to investigate the ACCmax in correlation with conventional non-invasive diagnostics in an in vivo setting. Methods: In twelve healthy individuals, an arterial stenosis was mimicked by compression on the common femoral artery by an ultrasounds probe, creating a local stenosis of 50%, 70% and 90%. The ABI, TBI, TP and several DUS parameters (including ACCmax) were assessed at the ankle during these different degrees of stenosis. All DUS parameters were measured separately by two observers to determine the interobserver variability. Results: Overall the ABI, TBI, TP, ACCmax, ACCsys and PSV decreased significantly when the degree of stenosis increased. The ACCmax showed the highest correlation with the degree of stenosis (r −.884), compared to ABI (r −.726), TBI (r −.716) and TP (r −.758). Furthermore, the interobserver variability of ACCmax was excellent, with an intraclass correlation coefficient (ICC) of.97. Conclusion: ACCmax is an accurate non-invasive DUS parameter to diagnose and assess the severity of a mimicked arterial stenosis in healthy individuals. Further prospective assessment of the clinical value of ACCmax and its potential benefits in patients with PAD is needed. [ABSTRACT FROM AUTHOR]

This literature review covers the choices to consider in training complex procedural, perceptual and motor skills. In particular, we focus on laparoscopic surgery. An overview is provided of important training factors modulating the acquisition, durability, transfer, and efficiency of trained skills. We summarize empirical studies and their theoretical background on the topic of training complex cognitive and motor skills that are pertinent to proficiency in laparoscopic surgery. The overview pertains to surgical simulation training for laparoscopy, but also to training in other demanding procedural and dexterous tasks, such as aviation, managing complex systems and sports. Evidence-based recommendations are provided for facilitating efficiency in laparoscopic motor skill training such as session spacing, adaptive training, task variability, part-task training, mental imagery and deliberate practice. [ABSTRACT FROM AUTHOR]

Background: To improve care for the injured service member, we have analyzed battle casualty patterns and mechanisms. This study is the first documented report of wounding patterns and mechanisms of battle casualties treated at the Dutch role 2 enhanced medical treatment facility at the multi-national base Tarin Kowt, Uruzgan, Afghanistan. Methods: Participants were selected from the trauma registry at the Dutch role 2 enhanced medical treatment facility if they fitted the criteria 'battle casualty' and 'disease non-battle injury' between August 2006 and August 2010. Results: The trauma registry query resulted in 2,736 casualties, of which 60 % ( N = 1,635) were classified as 'disease non-battle casualties' and 40 % ( N = 1,101) as 'battle casualties'. The battle casualties sustained 1,617 combat wounds, resulting in 1.6 wounds per battle casualty. These injuries were predominately caused by explosions (55 %) and gunshots (35 %). The wounding pattern was as follows: head and neck (21 %), thorax (13 %), abdomen (14 %), upper extremity (20 %), and lower extremity (33 %). Conclusions: The wounding patterns seen at the Dutch role 2 enhanced medical treatment facility at the multi-national base Tarin Kowt resemble the patterns as recorded by other coalition partners. The wounding patterns differ with previous conflicts: a greater proportion of head and neck wounds, and a lower proportion of truncal wounds. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES Total stripping of the great saphenous vein (GSV) is a validated surgical strategy of treating patients with primary varicose veins (PVV). An often cited, but not well documented and studied, complication of total stripping is postoperative damage of the saphenous nerve (SN). OBJECTIVE The objective was to evaluate the incidence of SN damage and to assess the therapeutic efficacy after total stripping of the GSV. MATERIALS AND METHODS Patients undergoing total stripping of the GSV because of PVV in the entire lower limb were enrolled. Pre- and postoperative neurologic examination was performed to identify potential sensory neurologic deficits. RESULTS Total stripping of the GSV in 69 limbs occurred because of pain (9%) or a tired feeling in the limbs (77%) or for cosmetic reasons (14%). The overall incidence of postoperative sensory neurologic deficits was 7 and 6%, respectively, after 6-week follow-up and both 3% after 3-month follow-up. In 99% of the patients, total stripping of the GSV resulted in reduction of the primary signs and symptoms. CONCLUSION The incidence of SN damage after total stripping of the GSV is low. Thus, total stripping of the GSV resulted in improvement of the primary complaint in almost all patients. Total stripping of the GSV is an effective surgical strategy in treating PVV. [ABSTRACT FROM AUTHOR]

Surgical training in the Netherlands has traditionally been characterized by learning on the job under the classic master-trainee doctrine. Over the past decades, it has become regionally organized with intensive structural training courses, and a peer-based quality control system. Recently, the nationwide programme has been modernized further and now involves a systematic, competency-based education with structural training courses, formalized assessment and room for reflection by residents under the supervision of surgical teaching groups. To this end, a uniform web-based digital portfolio is being introduced to facilitate monitoring of the individual resident's progress. Though requiring inspirational leadership, commitment, and determination, this modernization has sparked enthusiasm among trainees and teachers. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Social support may influence the seeking of appropriate treatment. We examined social support and peripheral arterial disease (PAD) severity as determinants of treatment for PAD in younger and older patients. Methods: Consecutive PAD patients (N=203) completed the Perceived Social Support Scale. Treadmill-walking distance and ankle–brachial pressure index (ABPI) were measured. The main outcome was invasive treatment for PAD in the year following diagnosis. Results: During follow-up, 48% of the patients underwent invasive treatment for PAD. Younger patients (≤64 years) tended to be more often invasively treated as compared to older patients. In younger patients, a high level of social support predicted invasive treatment above and beyond PAD severity. In older patients, low ABPI predicted invasive treatment. Conclusion: Younger patients with inadequate social support may fail to seek appropriate treatment, suggesting the need to consider psychosocial factors in optimizing treatment of atherosclerotic vascular disease in this high-risk group. [Copyright &y& Elsevier]

Patients with peripheral arterial disease (PAD) often experience diminishing quality of life (QOL) in many domains of their lives. However, factors associated with impaired QOL and perceived stress in these patients are not completely understood. The relative effects of disease status and type D (“distressed”) personality (tendencies to experience negative emotions and be socially inhibited) on these patient-based outcomes were examined. It has been argued that type D personality might depend on disease status; therefore, its effect was examined in a combined sample of 150 patients with PAD and 150 healthy controls. The Type D Scale–14, World Health Organization Quality of Life Assessment Instrument–100, and Perceived Stress Scale–10 Item assessed type D personality, QOL, and perceived stress, respectively. PAD severity (mild, moderate, or severe) was not associated with QOL or perceived stress. However, patients with PAD reported decreased QOL (p < 0.05) compared with healthy controls. Type D patients reported significantly poorer QOL than non–type D patients across PAD and healthy subgroups (p < 0.0001). After controlling for disease status (presence or absence of PAD), type D personality remained associated with increased risk for impaired QOL (odds ratio [OR] 7.35, 95% confidence interval [CI] 3.39 to 15.96, p < 0.0001) and perceived stress (OR 6.45, 95% CI 3.42 to 12.18, p < 0.0001). Hence, type D personality was associated with impaired QOL beyond the impairment already related to PAD and with increased stress in this high-risk population. In conclusion, type D personality is not merely a function of PAD but seems to represent a different determinant of patient-based outcomes. [Copyright &y& Elsevier]

Purpose: This study focusses on identifying values and preferences of patients, caregivers and healthcare professionals who have dealt with lower limb amputation for no-option chronic limb threatening ischemia. No-option chronic limb threatening ischemia is defined as limb ischemia for which no treatment options exist and where lower limb amputation is necessary in the short term. The values and preferences identified in this study can help improve decision-making processes. Patients and Methods: This was a qualitative study, using semi-structured interviews to gather data from patients, caregivers and healthcare professionals. Participants were selected from the patient and employee population of an academic medical center in The Netherlands. Nine patients and seven caregivers who dealt with lower limb amputation for no-option chronic limb threatening ischemia six to twelve months prior to the interview and were not cognitively impaired were selected. Nine healthcare professionals dealing with patients with no-option chronic limb threatening ischemia and lower limb amputation were selected. Results: Lower limb amputation was explicitly discussed late in the disease process, sometimes during an emergency setting. Patients stated goals were never discussed, healthcare professionals stated they were. The most important goal for patients was to live independently after lower limb amputation. Patients and caregivers feel healthcare professionals should be upfront about the possible necessity of lower limb amputation. Reasons to undergo lower limb amputation were absence of treatment options, pain and wanting to enjoy life again. Participants indicated accelerating lower limb amputation was not a viable option. Conclusion: All stakeholders reported overlapping values and preferences regarding main reasons for lower limb amputation, the primary goals after lower limb amputation, and the absence of a desire to accelerate lower limb amputation. The main difference in values and preferences is the preferred timing of discussing lower limb amputation. [ABSTRACT FROM AUTHOR]

Changing insights regarding radioiodine (I-131) administration in differentiated thyroid carcinoma (DTC) stir up discussions on the utility of pre-ablation diagnostic scintigraphy (DxWBS). Our retrospective study qualitatively and semi-quantitatively assessed posttherapy I-131 whole-body scintigraphy (TxWBS) data for thyroid remnant size and metastasis. Findings were associated with initial treatment success after nine months, as well as clinical, histopathological, and surgical parameters. Possible management changes were addressed. A thyroid remnant was reported in 89 of 97 (92%) patients, suspicion of lymph node metastasis in 26 (27%) and distant metastasis in 6 (6%). Surgery with oncological intent and surgery by two dedicated thyroid surgeons were independently associated with a smaller remnant. Surgery at a community hospital, aggressive tumor histopathology, histopathological lymph node metastasis (pN1) and suspicion of new lymph node metastasis on TxWBS were independently associated with an unsuccessful treatment. Thyroid remnant size was unrelated to treatment success. All 13 pN1 patients with suspected in situ lymph node metastases on TxWBS had an unsuccessful treatment, opposite 19/31 (61%) pN1 patients without (p = 0.009). Pre-ablative knowledge of these TxWBS findings had likely influenced management in 48 (50%) patients. Additional pre-ablative diagnostics could optimize patient-tailored I-131 administration. DxWBS should be considered, especially in patients with pN1 stage or suspected in situ lymph node metastasis. Dependent on local surgical expertise, DxWBS is not recommended to evaluate thyroid remnant size. [ABSTRACT FROM AUTHOR]

Background and aims: With the intention to gain support for the hypothesis that incident ischemic complications of atherosclerotic disease involve a stochastic aspect, we performed a histological, qualitative evaluation of the epidemiology of coronary atherosclerotic disease in a cohort of aortic valve donors. Patients and methods: Donors (n = 695, median age 54, range 11–65 years) were dichotomized into a non-cardiovascular (non-CVD) and a cardiovascular disease death (CVD) group. Consecutive 5 mm proximal left coronary artery segments were Movat stained, and the atherosclerotic burden for each segment was graded (revised AHA-classification). Results: Non-CVD and CVD groups showed steep increase of atherosclerosis severity beyond the age of 40, resulting in an endemic presence of advanced atherosclerosis in men over 40 and women over 50 years. In fact, only 19% of the non-CVD and 6% of the CVD donors over 40 years were classified with a normal LCA or a so called non-progressive lesion type. Fibrous calcified plaques (FCP), the consolidated remnants of earlier ruptured lesions, dominated in both non-CVD and CVD donors. Estimates of the atherosclerosis burden (i.e. average lesion grade, proportion of FCPs, and average number of FCPs per cross-section) were all higher in the CVD group (p<1.10−16, p<0.0001, and p<0.05, respectively). Conclusions: Dominance of consolidated FCP lesions in males over 40 and females over 50 years, show that plaque ruptures in the left coronary artery are common. However, the majority of these ruptures remain asymptomatic. This implies that the atherosclerotic process is repetitive. A relative difference in disease burden between CVD and non-CVD donors supports the concept that complications of atherosclerotic disease involve a stochastic element. [ABSTRACT FROM AUTHOR]

There are indications for elevated CXCL8 levels in abdominal aortic aneurysm disease (AAA). CXCL8 is concurrently involved in neutrophil-mediated inflammation and angiogenesis, two prominent and distinctive characteristics of AAA. As such we considered an evaluation of a role for CXCL8 in AAA progression relevant. ELISA’s, real time PCR and array analysis were used to explore CXCL8 signaling in AAA wall samples. A role for CXCL8 in AAA disease was tested through the oral CXCR1/2 antagonist DF2156A in the elastase model of AAA disease. There is an extreme disparity in aortic wall CXCL8 content between AAA and aortic atherosclerotic disease (median [IQR] aortic wall CXCL8 content: 425 [141–1261] (AAA) vs. 23 [2.8–89] (atherosclerotic aorta) µg/g protein (P < 1 · 10 −14 )), and abundant expression of the CXCR1 and 2 receptors in AAA. Array analysis followed by pathway analysis showed that CXCL8 hyper-expression in AAA is followed increased by IL-8 signaling (Z-score for AAA vs. atherosclerotic control: 2.97, p < 0.0001). Interference with CXCL8 signaling through DF2156A fully abrogated AAA formation and prevented matrix degradation in the murine elastase model of AAA disease (p < 0.001). CXCL8-signaling is a prominent and distinctive feature of AAA, interference with the pathway constitutes a promising target for medical stabilization of AAA. [ABSTRACT FROM AUTHOR]

Contemporary quality control methods are often insufficient in predicting clinical outcomes after revascularization in lower extremity arterial disease (LEAD) patients. This study evaluates the potential of near-infrared fluorescence imaging with indocyanine green to predict the clinical outcome following revascularization. Near-infrared fluorescence imaging was performed before and within 5 days following the revascularization procedure. Clinical improvement was defined as substantial improvement of pain free walking distance, reduction of rest- and/or nocturnal pain, or tendency toward wound healing. Time-intensity curves and 8 perfusion parameters were extracted from the dorsum of the treated foot. The quantified postinterventional perfusion improvement was compared within the clinical outcome groups. Successful near-infrared fluorescence imaging was performed in 72 patients (76 limbs, 52.6% claudication, 47.4% chronic limb-threatening ischemia) including 40 endovascular- and 36 surgical/hybrid revascularizations. Clinical improvement was observed in 61 patients. All perfusion parameters showed a significant postinterventional difference in the clinical improvement group (P-values <.001), while no significant differences were seen in the group without clinical improvement (P-values .168–.929). Four parameters demonstrated significant differences in percentage improvement comparing the outcome groups (P-values within .002–.006). Near-infrared fluorescence imaging has promising additional value besides clinical parameters for predicting the clinical outcome of revascularized LEAD patients. [ABSTRACT FROM AUTHOR]

Summary: Apart from donor and recipient risk factors, the effect of center‐related factors has significant impact on graft survival after liver transplantation (LT). To investigate this effect in Eurotransplant, a retrospective database analysis was performed, including all LT's in adult recipients (≥18 years) in the Eurotransplant region from 1.1.2007 until 31.12.2013. Additionally, a survey was sent out to all transplant centers requesting information on surgeons’ experience and exposure. In total, 10 265 LT's were included (median follow‐up 3.3 years), performed in 39 transplant centers. Funnel plots showed significant differences in graft survival between the transplant centers. After correction for donor and recipient risk, with the Eurotransplant donor risk index (ET‐DRI) and the simplified recipient risk index (sRRI) and random effects, these differences diminished. Mean historical volume (in the preceding 5 years) was a significant (P < 0.001), nonlinear marker for graft survival in the multivariate analysis. This study demonstrates that funnel plots can be used for benchmarking purposes in LT. Case‐mix correction can be performed with the use of the ET‐DRI and sRRI. The center effect encompasses the entire complex process of preoperative workup, operation to follow‐up. [ABSTRACT FROM AUTHOR]

Background: Guidelines advise periprocedural saline hydration for prevention of contrast induced-acute kidney injury (CI-AKI). We analysed whether 1-hour sodium bicarbonate hydration administered solely prior to intra-arterial contrast exposure is non-inferior to standard periprocedural saline hydration in chronic kidney disease (CKD) patients undergoing elective cardiovascular diagnostic or interventional contrast procedures. Methods: We performed an open-label multicentre non-inferiority trial between 2011–2014. Patients were randomized to 1 hour pre-procedure sodium bicarbonate hydration (250 ml 1.4%, N = 168) or 4–12 hours saline hydration (1000 ml 0.9%, N = 165) prior to and following contrast administration (2000 ml of saline total). Primary outcome was the relative serum creatinine increase (%) 48–96 hours post contrast exposure. Secondary outcomes were: incidence of CI-AKI (serum creatinine increase>25% or >44μmol/L), recovery of renal function, the need for dialysis, and hospital costs within two months follow-up. Results: Mean relative creatinine increase was 3.1% (95%CI 0.9 to 5.2%) in the bicarbonate and 1.1% (95%CI -1.2 to 3.5%) in the saline arm, mean difference 1.9% (95%CI -1.2 to 5.1%, p-non-inferiority <0.001). CI-AKI occurred in 11 (6.7%) patients randomized to sodium bicarbonate and 12 (7.5%) to saline (p = 0.79). Renal function did not fully recover in 40.0% and 44.4% of CI-AKI patients, respectively (p = 0.84). No patient required dialysis. Mean costs for preventive hydration and clinical preparation for the contrast procedure were $1158 for sodium bicarbonate vs. $1561 for saline (p < 0.001). Conclusion: Short hydration with sodium bicarbonate prior to elective cardiovascular diagnostic or therapeutic contrast procedures is non-inferior to standard periprocedural saline hydration in CKD patients with respect to renal safety and results in considerable healthcare savings. Trial registration: Netherlands Trial Register (), Nr NTR2699 [ABSTRACT FROM AUTHOR]

Background: An abdominal aortic aneurysm (AAA) is a progressive, generally symptomless disease that could ultimately result in a fatal rupture. Current guidelines advise conservative follow-up, and preventive surgical repair once the risk of rupture outweighs the cost of repair (55 mm in men). In developed countries, the majority of patients are diagnosed with AAAs less than 55 mm, and so enter a period of conservative surveillance. An important question is how patients perceive and cope with risk of rupture, AAA diagnosis and treatment, and presented AAA information. The goal of this study was to gain insight into patients' perceptions of conservative treatment for a small AAA to increase patient satisfaction. Methods: We conducted semistructured in-depth interviews and used questionnaires measuring health-related quality of life (RAND 36-Item Health Survey 1.0), illness-perceptions (Illness Perception Questionnaire - Revised), and anxiety and depression (Hospital Anxiety and Depression Scale). Interviews were audio recorded and transcript contents were analyzed based on grounded theory. Mean scores of the questionnaires were compared to (population) reference groups. Results: This study included ten male patients under surveillance for a small AAA from two hospitals in the Netherlands. Patients expressed no fear for AAA rupture, and also reported low levels of anxiety and depression in both the interviews and the Hospital Anxiety and Depression Scale. The presence of an AAA did not affect their social life or emotional wellbeing. The reported poorer physical health on RAND 36-Item Health Survey 1.0 presumably reflected common presence of comorbidities. Participants stated to that they were content with the frequency and setup of AAA surveillance. However, they generally lacked knowledge about AAA disease and/or treatment options. Conclusion: Conservative AAA follow-up ensures patients that the risks of AAA disease are limited. The vascular surgeon is the most important source of AAA information to patients, and patients fully rely on their vascular surgeon to take control in AAA treatment. [ABSTRACT FROM AUTHOR]

Background: Visual force feedback allows trainees to learn laparoscopic tissue manipulation skills. The aim of this experimental study was to find the most efficient visual force feedback method to acquire these skills. Retention and transfer validity to an untrained task were assessed.Methods: Medical students without prior experience in laparoscopy were randomized in three groups: Constant Force Feedback (CFF) (N = 17), Bandwidth Force Feedback (BFF) (N = 16) and Fade-in Force Feedback (N = 18). All participants performed a pretest, training, post-test and follow-up test. The study involved two dissimilar tissue manipulation tasks, one for training and one to assess transferability. Participants performed six trials of the training task. A force platform was used to record several force parameters.Results: A paired-sample t test showed overall lower force parameter outcomes in the post-test compared to the pretest (p < .001). A week later, the force parameter outcomes were still significantly lower than found in the pretest (p < .005). Participants also performed the transfer task in the post-test (p < .02) and follow-up (p < .05) test with lower force parameter outcomes compared to the pretest. A one-way MANOVA indicated that in the post-test the CFF group applied 50 % less Mean Absolute Nonzero Force (p = .005) than the BFF group.Conclusion: All visual force feedback methods showed to be effective in decreasing tissue manipulation force as no major differences were found between groups in the post and follow-up trials. The BFF method is preferred for it respects individual progress and minimizes distraction. [ABSTRACT FROM AUTHOR]

Background/objectives Carotid intimal media thickness (IMT) and coronary calcium scores (CCS) are thought to reflect atherosclerotic burden. The validity of this assumption for IMT is challenged by recent meta-analyses; for CCS by absence of a relationship between negative scores, and freedom of future events. As such, we considered evaluation of the relationship between tissue IMT and CCS, and extend of atherosclerotic disease relevant. Methods Analyses were performed on donor aortas obtained during renal graft procurement, and on coronary arteries collected during heart valve procurement for tissue donation. Movat pentachrome and Hematoxylin staining was performed, and the degree of atherosclerosis histologically graded. IMT and presence of calcium deposits were quantified on graded tissue sections. Results 304 aortas and 185 coronary arteries covering the full atherosclerotic spectrum were evaluated. Aortas and coronaries showed similar relationships between tissue IMT and degree of atherosclerosis, with gradual increase in tissue IMT during earlier phases of atherosclerosis (r = 0.68 and r = 0.30, P < 0.00001 for aorta and coronaries respectively), followed by plateauing of the curve in intermediate and advanced stages. Results for tissue IMT reveal high variability, resulting in wide confidence intervals. Results for CCS are similar for aorta and coronaries, with calcium depositions limited to advanced lesions. Conclusions Histological IMT measurements for the aorta and coronaries show large variations around the trend and plateauing of, and possibly reductions in IMT in late stage atherosclerotic disease. These observations for the aorta and coronaries may (partly) explain the limited benefit of including carotid IMT in risk prediction algorithms. [ABSTRACT FROM AUTHOR]

Background and aims An abdominal aortic aneurysm (AAA) is part of the atherosclerotic spectrum of diseases. The disease is hallmarked by a comprehensive localized inflammatory response with striking IL-6 hyperexpression. IL-6 is a multifaceted cytokine that, depending on the context, acts as a pro- or anti-inflammatory factor. In this study, we explore a putative role for IL-6 in AAA disease. Methods ELISA’s, Western blot analysis, real time PCR and array analysis were used to investigate IL-6 expression and signaling in aneurysm wall samples from patients undergoing elective AAA repair. A role for IL-6 in AAA disease was tested through IL-6 neutralization experiments (neutralizing antibody) in the elastase model of AAA disease. Results We confirmed an extreme disparity in aortic wall IL-6 content between AAA and atherosclerotic disease (median [5th–95th percentile] aortic wall IL-6 content: 281.6 [0.0–1820.8] (AAA) vs. 1.9 [0.0–37.8] μg/g protein (atherosclerotic aorta), ( p < 0.001). Array analysis followed by pathway analysis showed that IL-6 hyper-expression is followed by increased IL-6 signaling ( p < 0.000039), an observation confirmed by higher aneurysm wall pSTAT3 levels, and SOCS1 and SOCS3 mRNA expression, ( p < 0.018). Remarkably, preventive IL-6 neutralization i.e. treatment started one day prior to the elastase-induction resulted in >40% 7-day mortality due to aortic rupture. In contrast, delayed IL-6 neutralization (i.e. neutralization started at day 4 after elastase induction) did not result in ruptures, and quenched AAA growth ( p < 0.021). Conclusions AAA disease is characterized by increased IL-6 signaling. In the context of the elastase model of AAA disease, IL-6 appears a multi-faceted factor, protective upon acute injury, but negatively involved in the perpetuation of the disease process. [ABSTRACT FROM AUTHOR]

Background There's a large clinical need for novel vascular grafts. Tissue engineered blood vessels (TEBVs) have great potential to improve the outcome of vascular grafting procedures. Here, we present a novel approach to generate autologous TEBV in vivo . Polymer rods were engineered and implanted, evoking an inflammatory response that culminates in encapsulation by a fibrocellular capsule. We hypothesized that, after extrusion of the rod, the fibrocellular capsule differentiates into an adequate vascular conduit once grafted into the vasculature. Methods and results Rods were implanted subcutaneously in pigs. After 4 weeks, rods with tissue capsules grown around it were harvested. Tissue capsules were grafted bilaterally as carotid artery interposition. One and 4-week patency were evaluated by angiography whereupon pigs were sacrificed. Tissue capsules before and after grafting were evaluated on tissue remodeling using immunohistochemistry, RNA profiling and mechanical testing. Rods were encapsulated by thick, well-vascularized tissue capsules, composed of circumferentially aligned fibroblasts, collagen and few leukocytes, with adequate mechanical strength. Patency was 100% after 1 week and 87.5% after 4 weeks. After grafting, tissue capsules remodeled towards a vascular phenotype. Gene profiles of TEBVs gained more similarity with carotid artery. Wall thickness and αSMA-positive area significantly increased. Interestingly, a substantial portion of (myo)fibroblasts present before grafting expressed smooth muscle cell markers. While leukocytes were hardly present anymore, the lumen was largely covered with endothelial cells. Burst pressure remained stable after grafting. Conclusions Autologous TEBVs were created in vivo with sufficient mechanical strength enabling vascular grafting. Grafts differentiated towards a vascular phenotype upon grafting. [ABSTRACT FROM AUTHOR]

Background: In a combat environment, major vascular trauma endures as the leading cause of death. The Dutch role 2 Medical Treatment Facility (MTF), provided supportive care during the mission in Uruzgan, Afghanistan. Aim of this study was to conduct detailed analysis of the admitted major haemorrhages (vascular injuries) and to compare our findings with NATO coalition partners.Methods: Retrospective, descriptive study. Participants eligible for this study came from the role 2 MTF admission database, where they fitted the criteria 'Major haemorrhage (class 2 haemorrhage or more according to the ATLS(®) classification) between 2006 and 2010'. Results were contrasted with studies from coalition partners.Results: The query revealed 194 casualties sustaining 208 central (60% abdominal, 40% thoracic/neck), and 99 extremity major haemorrhages leading to 1.6 major haemorrhages per casualty. Survival was significantly better (p<0.05) in the peripheral vascular injuries cohort (96% versus 72%). Primary amputation was needed in 73/84 of lower, and in 8/15 of upper extremity major haemorrhages. Vascular repair or vascular Damage Control Surgery techniques (e.g. shunting) were used in 19/84 cases in the lower, and 7/15 in the upper extremity cohort, with a success rate of 69.2 percent. Amputation rates of coalition partners, using different inclusion and exclusion criteria, ranged from 5 to 60 percent.Conclusions: Only in a few cases genuine peripheral vascular surgery was needed (<1%). This limited number of reconstructions does not demonstrate the need for extensive skills in all areas of vascular surgery. Achieved success rate until discharge was almost 70%. Vascular damage control surgery seems effective as initial limb saving skill in a role 2 MTF. The difference in usage of definitions concerning vascular injuries in current literature warrants further assessment. For optimal analysis there is need for detailed (NATO wide) registration with uniform definitions for vascular injuries.Level Of Evidence: Level IV--Epidemiologic study. [ABSTRACT FROM AUTHOR]

Background: From August 2006-August 2010, as part of the ISAF mission, the Armed Forces of the Netherlands deployed a role 2 enhanced Medical Treatment Facility (R2E-MTF) to Uruzgan province, Afghanistan. Although from the principle doctrine not considered a primary task, care was delivered to civilians, including many children. Humanitarian aid accounted for a substantial part of the workload, necessitating medical, infrastructural, and logistical adaptations. Particularly pediatric care demanded specific expertise and equipment. In our pre-deployment preparations this aspect had been undervalued. Because these experiences could be influential in future mission planning, we analyzed our data and compared them with international reports. Methods: This is a retrospective, descriptive study. Using the hospital's electronic database, all pediatric cases, defined as patients <17 years of age, who were admitted between August 2006 and August 2010 to the Dutch R2E-MTF at Multinational Base Tarin Kowt (MBTK), Urzugan, Afghanistan were analyzed. Results: Of the 2736 admissions, 415 (15.2 %) were pediatric. The majority (80.9 %, 336/415) of these admissions were for surgical, often trauma-related, pathology and required 610 surgical procedures, being 26 % of all procedures. Mean length of stay was 3.1 days. The male to female ratio was 70:30. Girls were significantly younger of age than boys. In-hospital mortality was 5.3 %. Conclusion: Pediatric patients made up a considerable part of the workload at the Dutch R2E-MTF in Uruzgan, Afghanistan. This is in line with other reports from the recent conflicts in Iraq and Afghanistan, but used definitions in reported series are inconsistent, making comparisons difficult. Our findings stress the need for a comprehensive, prospective, and coalition-wide patient registry with uniformly applied criteria. Civilian disaster and military operational planners should incorporate reported patient statistics in manning documents, future courses, training manuals, logistic planning, and doctrines, because pediatric care is a reality that cannot be ignored. [ABSTRACT FROM AUTHOR]

Introduction Care for battle casualties demands special skills from medics, nurses, and tactical commanders. To date, no inventory has been performed evaluating the first responders (medics, nurses and tactical commanders) around battle casualties. Method This observational cohort study was conducted amongst the first responders ( n = 195) who were deployed to Southern Afghanistan (2009–2010) in three Marine companies. The survey focused on four main topics: (1) participants general background, (2) exposure to combat (casualty) situations, (3) self-perceived quality of care (1 [low]–10 [high]) in the pre-hospital phase, and (4) the effects of combat stressors on professional skills and social environment using the Post Deployment Reintegration Scale (PDRS) and the Impact of Event Scale-Revised (IES-R). Results 71% of the eligible Dutch tactical commanders, medics, and nurses participated in this survey. Most (14/16) medics and nurses scored their pre-deployment training as sufficient The overall self-perceived quality of care score was above average (7.8). Most (80%) of the participants were exposed to battle casualties. There were no significant differences regarding rank, gender, age and military task using the impact of event scale and PDRS, except for a worse score on the work negative, family positive and personal positive subscales ( p < 0.05) in the PDRS for the first responders in comparison to the armed forces norm score. Conclusion The quality of care in the pre-hospital phase was considered adequate, symptoms of post-traumatic stress in this group was low. Active involvement of co-combatants and the social support network are essential in adaption after exposure to combat events. Further research is necessary to identity predisposing preventable high stress factors, and to compose a “waterproof” aftercare programme. [ABSTRACT FROM AUTHOR]

Background The superior hypogastric plexus (SHP) is an autonomic plexus, located ventrally to the abdominal aorta and its bifurcation, innervating pelvic viscera. It is classically described as being composed of merely sympathetic fibres. However, post-operative complications after surgery damaging the peri-aortic retroperitoneal compartment suggest the existence of parasympathetic fibres. This immunohistochemical study describes the neuroanatomical composition of the human mature SHP. Material and methods Eight pre-determined retroperitoneal localizations including the lumbar splanchnic nerves, the SHP and the HN were studied in four human cadavers. Control tissues (white rami, grey rami, vagus nerve, splanchnic nerves, sympathetic ganglia, sympathetic chain and spinal nerve) were collected to verify the results. All tissues were stained with haematoxylin and eosin and antibodies S100, tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP) and myelin basic protein (MBP) to identify pre- and postganglionic parasympathetic and sympathetic nerve fibres. Results All tissues comprising the SHP and hypogastric nerves (HN) showed isolated expression of TH, VIP and MBP, revealing the presence of three types of fibres: postganglionic adrenergic sympathetic fibres marked by TH, unmyelinated VIP-positive fibres and myelinated preganglionic fibres marked by MBP. Analysis of control tissues confirmed that TH, VIP and MBP were well usable to interpret the neurochemical composition of the SHP and HN. Conclusion The human SHP and HN contain sympathetic and most likely postganglionic parasympathetic fibres. The origin of these fibres is still to be elucidated, however surgical damage in the peri-aortic retroperitoneal compartment may cause pelvic organ dysfunction related to both parasympathetic and sympathetic denervation. [ABSTRACT FROM AUTHOR]

Objectives: Units deployed to armed conflicts are at high risk for exposure to combat events. Many battle casualties (BCs) have been reported in the recent deployment to Afghanistan. The long-term impact of these combat injuries, at their five-year end point, is currently unknown. To date, no systematic inventory has been performed of an identified group of BCs in comparison to non-injured service members from the same operational theatre. Design: Observational cross-sectional cohort study. Setting: Open online survey among Dutch BCs that deployed to Afghanistan (2006–2010). Participants: The Dutch BCs (n = 62) were compared to two control groups of non-injured combat groups (battle exposed [n = 53], and non-battle exposed [n = 73]). Main Outcome Measures: Participants rated their impact of trauma exposure (Impact of Events [IES]), post deployment reintegration (Post Deployment Reintegration Scale [PDRS]), general symptoms of distress (Symptom Checklist 90 [SCL-90]), as well as their current perceived quality of life (EuroQol-6D [EQ-6D]). Also cost effectiveness (Short From health survey [SF-36]) and care consumption were assessed (Trimbos/iMTA questionnaire). Results: Over 90% of BCs were still in active duty. The mean scores of all questionnaires (IES, EQ-6D, SF-36, and SCL-90) of the BC group were significantly higher than in the control groups (p<0.05). The PDRS showed a significantly lower (p<0.05) outcome in the negative subscales. The mean consumption of care was triple that of both control groups. A lower score on quality of life was related to higher levels of distress and impact of trauma exposure. Conclusions: This study showed a clear long-term impact on a wide range of scales that contributes to a reduced quality of life in a group of BCs. Low perceived cost effectiveness matched with high consumption of care in the BC group in comparison to the control groups. These results warrant continuous monitoring of BCs. [ABSTRACT FROM AUTHOR]

Background: Independent of their blood pressure lowering effect, ACE inhibitors are thought to reduce vascular inflammation. The clinical relevance of this effect is unclear with the current knowledge. Abdominal aortic aneurysms (AAA) are characterized by a broad, non-specific inflammatory response, and thus provide a clinical platform to evaluate the anti-inflammatory potential of ACE inhibitors. Methods and Results: Eleven patients scheduled for open AAA repair received ramipril (5 mg/day) during 2–4 weeks preceding surgery. Aortic wall samples were collected during surgery, and compared to matched samples obtained from a biobank. An anti-inflammatory potential was evaluated in a comprehensive analysis that included immunohistochemistry, mRNA and protein analysis. A putative effect of ACE inhibitors on AAA growth was tested separately by comparing 18-month growth rate of patients on ACE inhibitors (n = 82) and those not taking ACE inhibitors (n = 204). Ramipril reduces mRNA expression of multiple pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF -α, Interferon-, and MCP-1, as well as aortic wall IL-8 and MCP-1 (P = 0.017 and 0.008, respectively) protein content. The is followed by clear effects on cell activation that included a shift towards anti-inflammatory macrophage (M2) subtype. Evaluation of data from the PHAST cohort did not indicate an effect of ACE inhibitors on 18-month aneurysm progression (mean difference at 18 months: −0.24 mm (95% CI: −0.90–0.45, P = NS). Conclusions: ACE inhibition quenches multiple aspects of vascular inflammation in AAA. However, this does not translate into reduced aneurysm growth. Trial Registration: Nederlands Trial Register . [ABSTRACT FROM AUTHOR]

Background: The patterns and mechanisms of injuries of all Dutch battle casualties (BCs) were analyzed to improve the care for injured service members. We performed an in-depth analysis of all Dutch BCs during the participation of The Netherlands as lead nation in the International Security Assistance Force mission in southern Afghanistan. Methods: Participants were selected from the trauma registry at the Dutch Role 2 Medical Treatment Facility if they met the criteria for Dutch BC between August 2006 and August 2010. Results: The trauma registry query resulted in 199 Dutch BCs. The battle injuries were predominantly caused by explosions (83.9 %). The case-fatality rate was 9.5 %: 16.5 % were killed in action, and 1.1 % died of wounds. The wounding pattern was as follows: head and neck (32.2 %), thorax (7.8 %), abdomen (12.7 %), upper extremity (17.6 %), lower extremity (29.7 %). The mean Abbreviated Injury Scale and Injury Severity Score were 3 (range 0-5) and 11 (range 1-43), respectively in the wounded-in-action group. Conclusions: Explosive devices accounted for almost 85 % of the casualties-much higher than in previous wars. Knowledge of the management of these injuries is also valuable in treating casualties from natural disasters or (terrorist) mass casualty situations. An integral multinational joint approach is highly recommended to develop more effective protective equipment and body armor. Prospective registration in a standardized system of data collection that encompasses all echelons of the medical support organization should be implemented. [ABSTRACT FROM AUTHOR]

Abstract: Background: The North Atlantic Treaty Organization (NATO) coalition forces remain heavily committed on combat operations overseas. Understanding the prevalence and characteristics of battlefield injury of coalition partners is vital to combat casualty care performance improvement. The aim of this systematic review was to evaluate the prevalence and characteristics of battle casualties from NATO coalition partners in Iraq and Afghanistan. The primary outcome was mechanism of injury and the secondary outcome anatomical distribution of wounds. Methods: This systematic review was performed based on all cohort studies concerning prevalence and characteristics of battlefield injury of coalition forces from Iraq and Afghanistan up to December 20th 2013. Studies were rated on the level of evidence provided according to criteria by the Centre for Evidence Based Medicine in Oxford. The methodological quality of observational comparative studies was assessed by the modified Newcastle-Ottawa Scale. Results: Eight published articles, encompassing a total of n =19,750 battle casualties, were systematically analyzed to achieve a summated outcome. There was heterogeneity among the included studies and there were major differences in inclusion and exclusion criteria regarding the target population among the included trials, introducing bias. The overall distribution in mechanism of injury was 18% gunshot wounds, 72% explosions and other 10%. The overall anatomical distribution of wounds was head and neck 31%, truncal 27%, extremity 39% and other 3%. Conclusions: The mechanism of injury and anatomical distribution of wounds observed in the published articles by NATO coalition partners regarding Iraq and Afghanistan differ from previous campaigns. There was a significant increase in the use of explosive mechanisms and a significant increase in the head and neck region compared with previous wars. [Copyright &y& Elsevier]

Introduction: Care for battle casualties demands special skills from surgeons and anesthesiologists. The experiences of Dutch military surgeons and anesthesiologists that deployed to South Afghanistan provided an opportunity to evaluate predeployment training and preparation of military medical specialists.Method: A survey was conducted among all surgeons and anesthesiologists (n = 40) that deployed to South Afghanistan between February 2006 and November 2010. They were asked about their medical preparedness, deployment experience, and postdeployment impact.Results: Most (35/40) participants reported high levels of preparedness before their deployment. All (40/40) surgeons and anesthesiologists described a positive influence of their deployment on their professional skills and 33/40 described a positive effect on their personal development. Knowledge of maxillofacial, ophthalmic, neurological, urological, gynecological, vascular, and thoracic surgery scored below average. Impact on mental health and social support network was reported as negative by 11/40 participants, 24/40 reported a neutral, and 5/40 a positive effect.Conclusion: A standardized predeployment training program to prepare Dutch surgeons and anesthesiologists for combat surgery is currently lacking. These results emphasize the need for a standardized predeployment medical training, despite high levels of perceived preparedness. Also, the high mental and psychological impact on the deployed surgeons and anesthesiologists warrants further assessment. [ABSTRACT FROM AUTHOR]

Aims: We investigated the role of the TLR4-accessory molecule RP105 (CD180) in post-ischemic neovascularization, i.e. arteriogenesis and angiogenesis. TLR4-mediated activation of pro-inflammatory Ly6Chi monocytes is crucial for effective neovascularization. Immunohistochemical analyses revealed that RP105+ monocytes are present in the perivascular space of remodeling collateral arterioles. As RP105 inhibits TLR4 signaling, we hypothesized that RP105 deficiency would lead to an unrestrained TLR4-mediated inflammatory response and hence to enhanced blood flow recovery after ischemia. Methods and Results: RP105−/− and wild type (WT) mice were subjected to hind limb ischemia and blood flow recovery was followed by Laser Doppler Perfusion Imaging. Surprisingly, we found that blood flow recovery was severely impaired in RP105−/− mice. Immunohistochemistry showed that arteriogenesis was reduced in these mice compared to the WT. However, both in vivo and ex vivo analyses showed that circulatory pro-arteriogenic Ly6Chi monocytes were more readily activated in RP105−/− mice. FACS analyses showed that Ly6Chi monocytes became activated and migrated to the affected muscle tissues in WT mice following induction of hind limb ischemia. Although Ly6Chi monocytes were readily activated in RP105−/− mice, migration into the ischemic tissues was hampered and instead, Ly6Chi monocytes accumulated in their storage compartments, bone marrow and spleen, in RP105−/− mice. Conclusions: RP105 deficiency results in an unrestrained inflammatory response and monocyte over-activation, most likely due to the lack of TLR4 regulation. Inappropriate, premature systemic activation of pro-inflammatory Ly6Chi monocytes results in reduced infiltration of Ly6Chi monocytes in ischemic tissues and in impaired blood flow recovery. [ABSTRACT FROM AUTHOR]

Background Guidelines recommend saline hydration for prophylaxis of contrast-induced acute kidney injury (CI-AKI) in patients with chronic kidney disease (CKD) undergoing intravenous contrast media-enhanced CT (CE-CT). The safety and efficacy of a brief hydration protocol using sodium bicarbonate in this population is unknown. We analysed whether 1-h sodium bicarbonate hydration prior to CE-CT is non-inferior to saline hydration prior to and after CE-CT in CKD patients. Methods We performed an open-label multicentre randomized trial. Patients were randomized to 250 mL of 1.4% sodium bicarbonate hydration prior to CE-CT or 1000 mL of 0.9% saline hydration prior to and, once again, after CE-CT. Primary outcome was the relative increase in serum creatinine 48–96 h post-CE-CT. Secondary outcomes were incidence of CI-AKI [serum creatinine increase >25%/>44 µmol/L (0.5 mg/dL)], recovery of renal function, the need for dialysis and 2-month hospital costs. Results Five hundred and seventy adult CKD patients undergoing CE-CT were randomized between 2010 and 2012, of whom 548 were included in the intention-to-treat population. Mean relative serum creatinine increase was 1.2% for sodium bicarbonate and 1.5% for saline (mean difference −0.3%; 95% confidence interval −2.7 to 2.1, P-value for non-inferiority <0.0001). CI-AKI occurred in 22 patients (4.1%); 8 (3.0%) randomized to sodium bicarbonate versus 14 (5.1%) to saline (P = 0.23). Renal function recovered in 75 and 69% of CI-AKI patients, respectively (P = 0.81). No patients developed a need for dialysis. Mean hydration costs per patient were €224 for the sodium bicarbonate and €683 for the saline regime (P < 0.001). Other healthcare costs were similar. Conclusions Short hydration with sodium bicarbonate prior to CE-CT was non-inferior to peri-procedural saline hydration with respect to renal safety and may result in healthcare savings. [Netherlands Trial Register (http://www.trialregister.nl/trialreg/index.asp), Nr 2149, date of registration 23 December 2009.] [ABSTRACT FROM AUTHOR]

In this study, we target the hypoxia inducible factor-1 alpha (HIF-1-alpha) pathway by short hairpin RNA interference therapy targeting prolyl hydroxylase-2 (shPHD2). We use the minicircle (MC) vector technology as an alternative for conventional nonviral plasmid (PL) vectors in order to improve neovascularization after unilateral hindlimb ischemia in a murine model. Gene expression and transfection efficiency of MC and PL, both in vitro and in vivo, were assessed using bioluminescence imaging (BLI) and firefly luciferase ( Luc) reporter gene. C57Bl6 mice underwent unilateral electrocoagulation of the femoral artery and gastrocnemic muscle injection with MC-shPHD2, PL-shPHD2, or phosphate-buffered saline (PBS) as control. Blood flow recovery was monitored using laser Doppler perfusion imaging, and collaterals were visualized by immunohistochemistry and angiography. MC-Luc showed a 4.6-fold higher in vitro BLI signal compared with PL-Luc. BLI signals in vivo were 4.3×105±3.3×105 (MC-Luc) versus 0.4×105±0.3×105 (PL-Luc) at day 28 ( p=0.016). Compared with PL-shPHD2 or PBS, MC-shPHD2 significantly improved blood flow recovery, up to 50% from day 3 until day 14 after ischemia induction. MC-shPHD2 significantly increased collateral density and capillary density, as monitored by alpha-smooth muscle actin expression and CD31+ expression, respectively. Angiography data confirmed the histological findings. Significant downregulation of PHD2 mRNA levels by MC-shPHD2 was confirmed by quantitative polymerase chain reaction. Finally, Western blot analysis confirmed significantly higher levels of HIF-1-alpha protein by MC-shPHD2, compared with PL-shPHD2 and PBS. This study provides initial evidence of a new potential therapeutic approach for peripheral artery disease. The combination of HIF-1-alpha pathway targeting by shPHD2 with the robust nonviral MC plasmid improved postischemic neovascularization, making this approach a promising potential treatment option for critical limb ischemia. [ABSTRACT FROM AUTHOR]

Background: Doxycycline inhibits formation and progression of abdominal aortic aneurysms (AAAs) in preclinical models of the disease, but it is unclear whether and how this observation translates to humans. Objective: To test whether doxycycline inhibits AAA progression in humans. Design: Randomized, placebo-controlled, double-blind trial. (Dutch Trial Registry: NTR 1345) SETTING: 14 Dutch hospitals. Patients: 286 patients with small AAAs between October 2008 and June 2011. Intervention: Daily dose of 100 mg of doxycycline (n = 144) or placebo (n = 142) for 18 months. Measurements: The primary outcome measure was aneurysm growth at 18 months, as estimated by repeated single-observer ultrasonography. Secondary outcomes included growth at 6 and 12 months and the need for elective surgery. Results: Mean aneurysm diameter (approximately 43 mm) and other baseline characteristics were similar in both groups. Doxycycline treatment was associated with increased aneurysm growth (4.1 mm in the doxycycline group vs. 3.3 mm in the placebo group at 18 months; difference, 0.8 mm [95% CI, 0.1 to 1.4 mm]; P = 0.016 mm). Twenty-one patients receiving doxycycline and 22 patients receiving placebo had elective surgical repair (Kaplan–Meier estimates were 16.1% for those receiving doxycycline and 16.5% for those receiving placebo; difference, -0.4% [CI, -9.3% to 8.5%]; P = 0.83). Time to repair was similar in the groups (P = 0.92). Limitations: This study focuses on patients with small AAAs. As such, whether the data can be extrapolated to larger AAAs (>55 mm) is unclear. The high number of elective repairs (n = 43) was unanticipated. Moreover, the study did not follow patients who withdrew because of an adverse effect. Conclusion: This trial found that 18 months of doxycycline therapy did not reduce aneurysm growth and did not influence the need for AAA repair or time to repair. Primary Funding Source: The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund. [ABSTRACT FROM AUTHOR]

Background: Doxycycline inhibits formation and progression of abdominal aortic aneurysms (AAAs) in preclinical models of the disease, but it is unclear whether and how this observation translates to humans. Objective: To test whether doxycycline inhibits AAA progression in humans. Design: Randomized, placebo-controlled, double-blind trial. (Dutch Trial Registry: NTR 1345) Setting: 14 Dutch hospitals. Patients: 286 patients with small AAAs between October 2008 and June 2011. Intervention: Daily dose of 100 mg of doxycycline (n 144) or placebo (n 142) for 18 months. Measurements: The primary outcome measure was aneurysm growth at 18 months, as estimated by repeated single-observer ultrasonography. Secondary outcomes included growth at 6 and 12 months and the need for elective surgery. Results: Mean aneurysm diameter (approximately 43 mm) and other baseline characteristics were similar in both groups. Doxycycline treatment was associated with increased aneurysm growth (4.1 mm in the doxycycline group vs. 3.3 mm in the placebo group at 18 months; difference, 0.8 mm [95% CI, 0.1 to 1.4 mm]; P 0.016 mm). Twenty-one patients receiving doxycycline and 22 patients receiving placebo had elective surgical repair (Kaplan–Meier estimates were 16.1% for those receiving doxycycline and 16.5% for those receiving placebo; difference, 0.4% [CI, 9.3% to 8.5%]; P 0.83). Time to repair was similar in the groups (P 0.92). Limitations: This study focuses on patients with small AAAs. As such, whether the data can be extrapolated to larger AAAs (55 mm) is unclear. The high number of elective repairs (n 43) was unanticipated. Moreover, the study did not follow patients who withdrew because of an adverse effect. Conclusion: This trial found that 18 months of doxycycline therapy did not reduce aneurysm growth and did not influence the need for AAA repair or time to repair. Primary Funding Source: The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this retrospective study was to assess the predictive performance of the American College of Surgeons (ACS) risk calculator for aortic aneurysm repair for the patient population of a Dutch tertiary referral hospital. Methods: This retrospective study included all patients who underwent elective endovascular or open aortic aneurysm repair at our institution between the years 2013 and 2019. Preoperative patient demographics and postoperative complication data were collected, and individual risk assessments were generated using five different current procedural terminology (CPT) codes. Receiver operating characteristic (ROC) curves, calibration plots, Brier scores, and Index of Prediction Accuracy (IPA) values were generated to evaluate the predictive performance of the ACS risk calculator in terms of discrimination and calibration. Results: Two hundred thirty-four patients who underwent elective endovascular or open aortic aneurysm repair were identified. Only five out of thirteen risk predictions were found to be sufficiently discriminative. Furthermore, the ACS risk calculator showed a structurally insufficient calibration. Most Brier scores were close to 0; however, comparison to a null model though IPA-scores showed the predictions generated by the ACS risk calculator to be inaccurate. Overall, the ACS risk calculator showed a consistent underestimation of the risk of complications. Conclusions: The ACS risk calculator proved to be inaccurate within the framework of endovascular and open aortic aneurysm repair in our medical center. To minimize the effects of patient selection and cultural differences, multicenter collaboration is necessary to assess the performance of the ACS risk calculator in aortic surgery. [ABSTRACT FROM AUTHOR]

Aims: In collateral development (i.e. arteriogenesis), mononuclear cells are important and exist as a heterogeneous population consisting of pro-inflammatory and anti-inflammatory/repair-associated cells. Protease-activated receptor (PAR)1 and PAR2 are G-protein-coupled receptors that are both expressed by mononuclear cells and are involved in pro-inflammatory reactions, while PAR2 also plays a role in repair-associated responses. Here, we investigated the physiological role of PAR1 and PAR2 in arteriogenesis in a murine hind limb ischemia model. Methods and Results: PAR1-deficient (PAR1-/-), PAR2-deficient (PAR2-/-) and wild-type (WT) mice underwent femoral artery ligation. Laser Doppler measurements revealed reduced post-ischemic blood flow recovery in PAR2-/- hind limbs when compared to WT, while PAR1-/- mice were not affected. Upon ischemia, reduced numbers of smooth muscle actin (SMA)-positive collaterals and CD31-positive capillaries were found in PAR2-/- mice when compared to WT mice, whereas these parameters in PAR1-/- mice did not differ from WT mice. The pool of circulating repair-associated (Ly6C-low) monocytes and the number of repair-associated (CD206-positive) macrophages surrounding collaterals in the hind limbs were increased in WT and PAR1-/- mice, but unaffected in PAR2-/- mice. The number of repair-associated macrophages in PAR2-/- hind limbs correlated with CD11b- and CD115-expression on the circulating monocytes in these animals, suggesting that monocyte extravasation and M-CSF-dependent differentiation into repair-associated cells are hampered. Conclusion: PAR2, but not PAR1, is involved in arteriogenesis and promotes the repair-associated response in ischemic tissues. Therefore, PAR2 potentially forms a new pro-arteriogenic target in coronary artery disease (CAD) patients. [ABSTRACT FROM AUTHOR]

Aims Failure of vein graft conduits due to vein graft thickening, accelerated atherosclerosis, and subsequent plaque rupture is applicable to 50% of all vein grafts within 10 years. New potential therapeutic targets to treat vein graft disease may be found in components of the innate immune system, such as mast cells and complement factors, which are known to be involved in atherosclerosis and plaque destabilization. Interestingly, mast cells can be activated by complement factor C5a and, therefore, a direct role for C5a-mediated mast cell activation in vein graft disease is anticipated. We hypothesize that C5a-mediated mast cell activation is involved in the development and destabilization of vein graft lesions. Methods and results Mast cells accumulated in time in murine vein graft lesions, and C5a and C5a-receptor (CD88) expression was up-regulated during vein graft disease in apolipoprotein E-deficient mice. Mast cell activation with dinitrophenyl resulted in a profound increase in vein graft thickening and in the number of plaque disruptions. C5a application enhanced vein graft lesion formation, while treatment with a C5a-receptor antagonist resulted in decreased vein graft disease. C5a most likely exerts its function via mast cell activation since the mast cell inhibitor cromolyn totally blocked C5a-enhanced vein graft disease. Conclusion These data provide evidence that complement factor C5a-induced mast cell activation is highly involved in vein graft disease, which identifies new targets to prevent vein graft disease. [ABSTRACT FROM AUTHOR]

The current study describes the incidence and phenotype of plaque rupture complications in murine vein grafts. Since matrix metalloproteinases (MMPs) are highly involved in atherosclerotic plaque vulnerability and plaque rupture, we hypothesized that this model can be validated by overexpression of the MMP inhibitor TIMP-1. First we studied 47 vein grafts in hypercholesterolemic ApoE3*Leiden mice for the incidence of plaque complications. In 79% of these grafts, extensive lesions with plaque rupture complications like dissections, intraplaque hemorrhages or erosions with intramural thrombi were found. Next, in vivo Near-InfraRed-Fluorescence imaging demonstrated that electroporation mediated TIMP- 1-overexpression reduced local MMP activity in vein grafts by 73% (p,0.01). This led to a 40% reduction in lesion-size after 28d (p = 0.01) and a more stable lesion phenotype with significant more smooth muscle cells (135%), collagen (47%) and significant less macrophages (44%) and fibrin (55%) than controls. More importantly, lesions in the TIMP-1 group showed a 90% reduction of plaque complications (10/18 of control mice showed plaque complications versus 1/18 in TIMP-1 treated mice). Murine vein grafts are a relevant spontaneous model to study plaque stability and subsequent hemorrhagic complications, resulting in plaque instability. Moreover, inhibition of MMPs by TIMP-1-overexpression resulted in decreased plaque progression, increased stabilization and decreased plaque rupture complications in murine vein grafts. [ABSTRACT FROM AUTHOR]

Background: Acute appendicitis continues to be a challenging diagnosis. Preoperative radiological imaging using ultrasound (US) or computed tomography (CT) has gained popularity as it may offer a more accurate diagnosis than classic clinical evaluation. The optimal implementation of these diagnostic modalities has yet to be established. The aim of the present study was to investigate a diagnostic pathway that uses routine US, limited CT, and clinical re-evaluation for patients with acute appendicitis. Methods: A prospective analysis was performed of all patients presenting with acute abdominal pain at the emergency department from June 2005 until July 2006 using a structured diagnosis and management flowchart. Daily practice was mimicked, while ensuring a valid assessment of clinical and radiological diagnostic accuracies and the effect they had on patient management. Results: A total of 802 patients were included in this analysis. Additional radiological imaging was performed in 96.3% of patients with suspected appendicitis ( n = 164). Use of CT was kept to a minimum (17.9%), with a US:CT ratio of approximately 6:1. Positive and negative predictive values for the clinical diagnosis of appendicitis were 63 and 98%, respectively; for US 94 and 97%, respectively; and for CT 100 and 100%, respectively. The negative appendicitis rate was 3.3%, the perforation rate was 23.5%, and the missed perforated appendicitis rate was 3.4%. No (diagnostic) laparoscopies were performed. Conclusions: A diagnostic pathway using routine US, limited CT, and clinical re-evaluation for patients with acute abdominal pain can provide excellent results for the diagnosis and treatment of appendicitis. [ABSTRACT FROM AUTHOR]

Purpose: To compare the accuracy of computed tomography (CT) analyzed by individual radiology staff members and body imaging radiologists in a non-academic teaching hospital for the diagnosis of acute appendicitis. Patients and Methods: In a prospective study 199 patients with suspected acute appendicitis were examined with unenhanced CT. CT images were pre-operatively analyzed by one of the 12 members of the radiology staff. In a later stage two body imaging radiologist reassessed all CT images without knowledge of the surgical findings and without knowledge of the primary CT diagnosis. The results, independently reported, were correlated with surgical and histopathologic findings. Results: In 132 patients (66%) acute appendicitis was found at surgery, in 67 patients (34%) a normal appendix was found. The sensitivity of the primary CT analysis and of the reassessment was 76% and 88%, respectively; the specificity was 84% and 87%; the positive predictive value was 90% and 93%; the negative predictive value was 64% and 78%; and the accuracy was 78% and 87%. Conclusion: Reassessment of CT images for acute appendicitis by body imaging radiologists results in a significant improvement of sensitivity, negative predictive value and accuracy. To prevent false-negative interpretation of CT images in acute appendicitis the expertise of the attending radiologist should be considered. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To compare the accuracy of computed tomography (CT) analyzed by individual radiology staff members and body imaging radiologists in a non-academic teaching hospital for the diagnosis of acute appendicitis. Patients and methods: In a prospective study 199 patients with suspected acute appendicitis were examined with unenhanced CT. CT images were pre-operatively analyzed by one of the 12 members of the radiology staff. In a later stage two body imaging radiologist reassessed all CT images without knowledge of the surgical findings and without knowledge of the primary CT diagnosis. The results, independently reported, were correlated with surgical and histopathologic findings. Results: In 132 patients (66%) acute appendicitis was found at surgery, in 67 patients (34%) a normal appendix was found. The sensitivity of the primary CT analysis and of the reassessment was 76% and 88%, respectively; the specificity was 84% and 87%; the positive predictive value was 90% and 93%; the negative predictive value was 64% and 78%; and the accuracy was 78% and 87%. Conclusion: Reassessment of CT images for acute appendicitis by body imaging radiologists results in a significant improvement of sensitivity, negative predictive value and accuracy. To prevent false-negative interpretation of CT images in acute appendicitis the expertise of the attending radiologist should be considered. [Copyright &y& Elsevier]

Multiple endocrine neoplasia type 2 (MEN 2) is caused by a RET mutation in chromosome 10. All MEN 2 patients develop medullary thyroid carcinoma (MTC). The age-related risk of MTC is associated with the type of RET mutation. Our aim was to identify prognostic factors associated with recurrent MTC in MEN 2 patients. In a nationwide case–control study, all patients who underwent total thyroidectomy in the Netherlands under the age of 20 years were classified into standard (1), high (2), or very high risk (3) for MTC based on RET-mutation type. Disease-free patients were compared with those with recurrent disease. A total of 93 patients were included in the study. Sixty-six percent had MTC on histology, the youngest being 1 year old. Codon 634 was most affected. Sixteen (18%) patients had persistent or recurrent disease, one of whom died. Significantly associated determinants of outcome in univariate analysis were higher age at surgery, no age-appropriate prophylactic surgery according to risk level, elevated preoperative calcitonin levels, affected codon, and the presence of lymph node metastases at surgery. On multivariate analysis only age of surgery was the single independent factor associated with persistent disease. Prophylactic thyroidectomy beyond the recommended age is associated with persistent/recurrent disease. In addition, codon 634 mutation is associated with a high risk of recurrence requiring early surgery for all these patients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the efficacy and safety of standard outpatient re-evaluation for patients who are not admitted to the hospital after emergency department surgical consultation for acute abdominal pain. All patients seen at the emergency department between June 2005 and July 2006 for acute abdominal pain were included in a prospective study using a structured diagnosis and management flowchart. Patients not admitted to the hospital were given appointments for re-evaluation at the outpatient clinic within 24 h. All clinical parameters, radiological results, diagnostic considerations, and management proposals were scored prospectively. Five-hundred patients were included in this analysis. For 148 patients (30%), the final diagnosis was different from the diagnosis after initial evaluation. Eighty-five patients (17%) had a change in management after re-evaluation, and 20 of them (4%) were admitted to the hospital for an operation. Only 6 patients (1.2%) had a delay in diagnosis and treatment, which did not cause extra morbidity. Standard outpatient re-evaluation is a safe and effective means of improving diagnostic accuracy and helps to adapt management for patients that are not admitted to the hospital after surgical consultation for acute abdominal pain at the emergency department. [ABSTRACT FROM AUTHOR]