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Draaien van de arm: bij hoe vaak per dag spreek je van ‘hoge blootstelling op werk’ en ‘kans op arbeidsgebonden overbelastingsletsel van de laterale epicondylitis of tenniselleboog’? Dr. Paul Kuijer en collega’s vatten het uitgebreide artikel hieronder samen.

Background : The field of trauma and traumatic stress is dominated by studies on treatments for those who experience adversity from traumatic experiences. While this is important, we should not neglect the opportunity to consider trauma in a public health perspective. Such a perspective will help to develop prevention approaches as well as extend the reach of early interventions and treatments. The purpose of this paper is to provide an introduction to a public health approach to trauma and traumatic stress and identify key opportunities for trauma professionals and our professional societies (such as the International Society for Traumatic Stress Studies [ISTSS] and the European Society for Traumatic Stress Studies [ESTSS]) to increase our societal impact by adopting such an approach. Method : This paper reviews and summarizes key findings related to the public health impact of trauma. The special case of children is explored, and a case example of the Norwegian terrorist attacks in 2011 illustrates the potential for improving our response to community level traumatic events. We also discuss how professional organizations such as ESTSS and ISTSS, as well as individual trauma professionals, can and should play an important role in promoting a public health approach. Results : Trauma is pervasive throughout the world and has negative impacts at the personal, family, community, and societal levels. A public health perspective may help to develop prevention approaches at all of these levels, as well as extend the reach of early interventions and treatments. Conclusions : Professional organizations such as ESTSS and ISTSS can and should play an important role in promoting a public health approach. They should promote the inclusion of trauma in the global public health agenda and include public health in their activities. Keywords: Posttraumatic stress disorder; trauma; prevention; public health (Published: 18 March 2016) Responsible Editor: Marit Sijbrandij, VU University, Netherlands. This paper is part of the Special Issue: Trauma occurs in social contexts. More papers from this issue can be found at www.ejpt.net For the abstract or full text in other languages, please see Supplementary files in the column to the right (under ‘Article Tools’). Citation: European Journal of Psychotraumatology 2016, 7 : 29715 - http://dx.doi.org/10.3402/ejpt.v7.29715

Background and purpose There are concerns that the coronavirus disease 2019 (COVID-19) outbreak negatively affects the quality of care for acute cardiovascular conditions. We assessed the impact of the COVID-19 outbreak on trends in hospital admissions and workflow parameters of acute stroke care in Amsterdam, The Netherlands. Methods We used data from the three hospitals that provide acute stroke care for the Amsterdam region. We compared two 7-week periods: one during the peak of the COVID-19 outbreak (March 16th–May 3th 2020) and one prior to the outbreak (October 21st–December 8th 2019). We included consecutive patients who presented to the emergency departments with a suspected stroke and assessed the change in number of patients as an incidence-rate ratio (IRR) using a Poisson regression analysis. Other outcomes were the IRR for stroke subtypes, change in use of reperfusion therapy, treatment times, and in-hospital complications. Results During the COVID-19 period, 309 patients presented with a suspected stroke compared to 407 patients in the pre-COVID-19 period (IRR 0.76 95%CI 0.65–0.88). The proportion of men was higher during the COVID-19 period (59% vs. 47%, p p = 0.58) or endovascular thrombectomy (11% vs 12%, p = 0.82) or associated treatment times. Seven patients (all ischemic strokes) were diagnosed with COVID-19. Conclusion We observed a 24% decrease in suspected stroke presentations during the COVID-19 outbreak, but no evidence for a decrease in quality of acute stroke care.

Background and Aims Almost all patients with familial adenomatous polyposis (FAP) develop duodenal adenomas, with a 4% to 18% risk of progression into duodenal cancer. Prophylactic endoscopic resection of duodenal adenomas may prevent cancer and is considered safer than surgical alternatives; however, data are limited. Therefore, the aim of this study was to assess safety and effectiveness of endoscopic duodenal interventions in patients with FAP. Methods We performed a historical cohort study including patients with FAP who underwent an endoscopic duodenal intervention between 2002 and 2018. Safety was defined as adverse event rate per intervention and effectiveness as duodenal surgery–free and duodenal cancer–free survival. Change in Spigelman stage was assessed as a secondary outcome. Results In 68 endoscopy sessions, 139 duodenal polypectomies were performed in 49 patients (20 men; median age, 43). Twenty-nine patients (14 men; median age, 49) underwent a papillectomy. After polypectomy, 9 (13%) bleedings and 1 (2%) perforation occurred, all managed endoscopically. Six (21%) bleedings (endoscopically managed), 4 (14%) cases of pancreatitis, and 1 (3%) perforation (conservatively treated) occurred after papillectomy. Duodenal surgery–free survival was 74% at 89 months after polypectomy and 71% at 71 months after papillectomy; no duodenal cancers were observed. After a median of 18 months (interquartile range, 10-40; range, 3-121) after polypectomy, Spigelman stages were significantly lower (P Conclusions In our FAP patients, prophylactic duodenal polypectomies were relatively safe. Papillectomies showed substantial adverse events, suggesting its benefits and risk should be carefully weighted. Both were effective, however, because surgical interventions were limited and none developed duodenal cancer.

Purpose This study aimed to validate the PROMIS Pediatric item bank v2.0 Peer Relationships and compare reliability of the full item bank to its short form, computerized adaptive test (CAT) and the social functioning (SF) subscale of the Pediatric Quality of Life Inventory (PedsQL™). Methods Children aged 8–18 (n = 1327), representative of the Dutch population completed the Peer Relationships item bank. A graded response model (GRM) was fit to the data. Structural validity was assessed by checking item-fit statistics (S-X2, p 0.50) was expected between Peer Relationships and the PedsQL SF subscale. Cross-cultural DIF between U.S. and NL was assessed using logistic regression, where an item with McFadden’s pseudo R2 > 0.02 was considered to have DIF. Percentage of participants reliably measured was assessed using the standard error of measurement (SEM) 2)/nitems) was calculated to compare how well the instruments performed relative to the amount of items administered. Results In total, 527 (response rate: 39.7%) children completed the PROMIS v2.0 Peer Relationships item bank (nitems = 15) and the PedsQL™ (nitems = 23). Structural validity of the Peer Relationships item bank was sufficient, but one item displayed misfit in the GRM model (S-X2 R2 = 0.0253). The item bank correlated moderately high (r = 0.61) with the PedsQL SF subscale Reliable measurements were obtained at the population mean and > 2SD in the clinically relevant direction. CAT outperformed all other measures in efficiency. Mean T-score of the Dutch general population was 46.9(SD 9.5). Conclusion The pediatric PROMIS Peer Relationships item bank was successfully validated for use within the Dutch population and reference data are now available.

BACKGROUND: Structured work support needs assessment could facilitate professionals and increase assessment consistency. OBJECTIVES: Evaluating usability of the Work Support Needs Assessment Tool and test if professionals’ (labour experts, coaches) findings become more consistent after a tool training. The tool includes a 21 item checklist for assessing work support needs of people with disabilities. METHODS: Usability was explored through 28 interviews with professionals. Consistency was evaluated in an experimental pre-post study design, in which thirty-nine other professionals assessed work support needs of standardized clients before and after a protocolized training. Quantitative content analysis was conducted. Consistency of findings between professionals covered three categories: type (client-focused coaching), focus (topics to be addressed) and duration of support. An increase in consistency was defined as a decrease in the total number of different sub-categories of findings in each category. RESULTS: Nineteen professionals indicated that the tool was useful, as they gained relevant information and insights. Regarding consistency, the number of findings differed pre- and post-training for type of support (8 vs 9) and focus of support (18 vs 15 and 18 vs 17). CONCLUSIONS: Participants had positive experiences with the tool. Increased consistency in findings of professionals after the training was not demonstrated with the current study design.

BACKGROUND AND OBJECTIVE: New diagnostic tests to identify a well-established disease state must undergo a series of scientific studies from test construction to finally demonstrating a societal impact. Traditionally, these studies are performed with substantial time gaps in between, resulting in a long time period from the initial idea to roll out in clinical practice including reimbursement. Seamless designs allowing us to combine a sequence of studies in one protocol may hence accelerate this process. Currently, a systematic investigation of the potential of seamless designs in diagnostic research is lacking.METHODS: We identify major study types in diagnostic research and their basic characteristics with respect to the application of seamless designs. This information is used to identify major hurdles and opportunities for seamless designs.RESULTS: The following major study types were identified: Variable construction studies, cut point finding studies, variable value studies, single-arm accuracy studies, comparative accuracy studies, change-in-management studies, observational discordant pair studies, randomized discordant pair studies, and randomized diagnostic studies. The following characteristics were identified: Type of recruitment (case-control vs. population-based), application of a reference standard, inclusion of a comparator, paired or unpaired application of a comparator, assessment of patient-relevant outcomes, and possibility for blinding of test results. Two basic hurdles could be identified: 1) Accuracy studies are hard to combine with postaccuracy studies in a seamless design for the following reasons. First, because the former are required to justify the latter and application of a reference test in outcome studies may be a threat to the integrity of the study. 2) Randomized diagnostic studies are probably best placed as singular studies at the end of the process, as all other questions should be clarified before performing such a study. However, otherwise there is a substantial potential for seamless designs. All steps from the construction to the comparison with the comparator can be combined in one protocol. This may include a switch from case-control to population-based recruitment as well as a switch from a single-arm study to a comparative accuracy study. In addition, change-in-management studies can be combined with an outcome study in discordant pairs.CONCLUSION: There is a potential for seamless designs in diagnostic research. It is wise to have the whole sequence of necessary studies in mind and to plan a full programme than rather individual studies one by one.

Introduction: There is little evidence to guide the timing of delivery of women with early-onset severe preeclampsia. We hypothesize that immediate delivery is not inferior for neonatal outcome but reduces maternal complications compared with temporizing management. Material and methods: This Dutch multicenter open-label randomized clinical trial investigated non-inferiority for neonatal outcome of temporizing management as compared with immediate delivery (TOTEM NTR 2986) in women between 27+5 and 33+5 weeks of gestation admitted for early-onset severe preeclampsia with or without HELLP syndrome. In participants allocated to receive immediate delivery, either induction of labor or cesarean section was initiated at least 48 hours after admission. Primary outcomes were adverse perinatal outcome, defined as a composite of severe respiratory distress syndrome, bronchopulmonary dysplasia, culture proven sepsis, intraventricular hemorrhage grade 3 or worse, periventricular leukomalacia grade 2 or worse, necrotizing enterocolitis stage 2 or worse, and perinatal death. Major maternal complications were secondary outcomes. It was estimated 1130 women needed to be enrolled. Analysis was by intention-to-treat. Results: The trial was halted after 35 months because of slow recruitment. Between February 2011 and December 2013, a total of 56 women were randomized to immediate delivery (n = 26) or temporizing management (n = 30). Median gestational age at randomization was 30 weeks. Median prolongation of pregnancy was 2 days (interquartile range 1-3 days) in the temporizing management group. Mean birthweight was 1435 g after immediate delivery vs 1294 g after temporizing management (P =.14). The adverse perinatal outcome rate was 55% in the immediate delivery group vs 52% in the temporizing management group (relative risk 1.06; 95% confidence interval 0.67-1.70). In both groups there was one neonatal death and no maternal deaths. In the temporizing treatment group, one woman experienced pulmonary edema and one placental abruption. Analyses of only the singleton pregnancies did not result in other outcomes. Conclusions: Early termination of the trial precluded any conclusions for the main outcomes. We observed that temporizing management resulted in a modest prolongation of pregnancy without changes in perinatal and maternal outcome. Conducting a randomized study for this important research question did not prove feasible.

Aim: Although has been suggested that an appendectomy has a positive effect on the disease course in patients with ulcerative colitis (UC), recent studies indicate a potential increase in risk of colectomy and colorectal cancer (CRC). This study aimed to evaluate the rates of colectomy and CRC after appendectomy in UC patients using a nationwide prospective database [the Initiative on Crohn and Colitis Parelsnoer Institute – Inflammatory Bowel Disease (ICC PSI-IBD) database]. Method: All UC patients were retrieved from the ICC PSI-IBD database between January 2007 and May 2018. Primary outcomes were colectomy and CRC. Outcomes were compared in patients with and without appendectomy, with a separate analysis for timing of appendectomy (before or after UC diagnosis). Results: A total of 826 UC patients (54.7% female; median age 46 years, range 18–89 years) were included. Sixty-three (7.6%) patients had previously undergone appendectomy: 24 (38.1%) before and 33 (52.4%) after their diagnosis of UC. In multivariate analysis, appendectomy after UC diagnosis was associated with a significantly lower colectomy rate compared with no appendectomy [hazard ratio (HR) 0.16, 95% C: 0.04–0.66, P = 0.011], and the same nonsignificant trend was seen in patients with an appendectomy before UC diagnosis (HR 0.35, 95% CI 0.08–1.41, P = 0.138). Appendectomy was associated with delayed colectomy, particularly when it was performed after diagnosis of UC (P = 0.009). No significant differences were found in the CRC rate between patients with and without appendectomy (1.6% vs 1.2%; P = 0.555). Conclusion: Appendectomy in established UC is associated with an 84% decreased risk of colectomy and a delay in surgery. Since the colon is in situ for longer, the risk of developing CRC remains, which underscores the importance of endoscopic surveillance programmes.

Introduction: When an HIV cure becomes available, it will have consequences for people living with HIV (PLHIV) and key populations who are vulnerable to HIV. This qualitative study aimed to explore the perceived impact of two HIV cure scenarios (post-treatment control when HIV is suppressed without the need for ongoing antiretroviral treatment (ART) and complete HIV elimination) on the quality of life of PLHIV and key populations living without HIV in the Netherlands.Methods: Participants were purposefully sampled from the Amsterdam Cohort Studies, the AGEhIV Cohort Study, the outpatient clinic of the University Medical Centre Utrecht and the Dutch HIV Association to increase variability. Semi-structured in-depth interviews were conducted between October 2020 and March 2021 and thematically analysed.Results: Of the 42 interviewed participants, 29 were PLHIV and 13 represented key populations (i.e., men who have sex with men and people injecting drugs). Both PLHIV and participants from vulnerable key populations hoped that a cure would result in normalization of their lives by removing the need to disclose HIV, reducing stigma and guilt, increasing independence of ART, and liberating sexual behaviour. Both groups believed only HIV elimination could accomplish this desired impact.Conclusions: While the post-treatment control scenario seems a more plausible outcome of current HIV cure research, our findings highlight that participants may not perceive it as a true cure. Involvement of PLHIV and vulnerable key populations in devising acceptable and feasible experimental approaches to HIV cure is essential to ensure their future successful implementation.

Aims Familial hypercholesterolaemia (FH) predisposes children to the early initiation of atherosclerosis and is preferably diagnosed by DNA analysis. Yet, in many children with a clinical presentation of FH, no mutation is found. Adult data show that high levels of lipoprotein(a) [Lp(a)] may underlie a clinical presentation of FH, as the cholesterol content of Lp(a) is included in conventional LDL cholesterol measurements. As this is limited to adult data, Lp(a) levels in children with and without (clinical) FH were evaluated. Methods and results Children were eligible if they visited the paediatric lipid clinic (1989–2020) and if Lp(a) measurement and DNA analysis were performed. In total, 2721 children (mean age: 10.3 years) were included and divided into four groups: 1931 children with definite FH (mutation detected), 290 unaffected siblings/normolipidaemic controls (mutation excluded), 108 children with probable FH (clinical presentation, mutation not detected), and 392 children with probable non-FH (no clinical presentation, mutation not excluded). In children with probable FH, 32% were found to have high Lp(a) [geometric mean (95% confidence interval) of 15.9 (12.3–20.6) mg/dL] compared with 10 and 10% [geometric means (95% confidence interval) of 11.5 (10.9–12.1) mg/dL and 9.8 (8.4–11.3) mg/dL] in children with definite FH (P = 0.017) and unaffected siblings (P = 0.002), respectively. Conclusion Lp(a) was significantly higher and more frequently elevated in children with probable FH compared with children with definite FH and unaffected siblings, suggesting that high Lp(a) may underlie the clinical presentation of FH when no FH-causing mutation is found. Performing both DNA analysis and measuring Lp(a) in all children suspected of FH is recommended to assess possible LDL cholesterol overestimation related to increased Lp(a).

Background By binding to negatively charged polysaccharides called glycosaminoglycans, sodium can be stored in the body—particularly in the skin—without concurrent water retention. Concordantly, individuals with changed glycosaminoglycan structure (e.g. type 1 diabetes (DM1) and hereditary multiple exostosis (HME) patients) may have altered sodium and water homeostasis. Methods We investigated responses to acute (30-min infusion) and chronic (1-week diet) sodium loading in 8 DM1 patients and 7 HME patients in comparison to 12 healthy controls. Blood samples, urine samples, and skin biopsies were taken to investigate glycosaminoglycan sulfation patterns and both systemic and cellular osmoregulatory responses. Results Hypertonic sodium infusion increased plasma sodium in all groups, but more in DM1 patients than in controls. High sodium diet increased expression of nuclear factor of activated t-cells 5 (NFAT5)—a transcription factor responsive to changes in osmolarity—and moderately sulfated heparan sulfate in skin of healthy controls. In HME patients, skin dermatan sulfate, rather than heparan sulfate, increased in response to high sodium diet, while in DM1 patients, no changes were observed. Conclusion DM1 and HME patients show distinct osmoregulatory responses to sodium loading when comparing to controls with indications for reduced sodium storage capacity in DM1 patients, suggesting that intact glycosaminoglycan biosynthesis is important in sodium and water homeostasis. Trial registration These trials were registered with the Netherlands trial register with registration numbers: NTR4095 (https://www.trialregister.nl/trial/3933 at 2013-07-29) and NTR4788 (https://www.trialregister.nl/trial/4645 at 2014-09-12).

PURPOSE: Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. METHODS: We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. RESULTS: Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). CONCLUSION: Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF. ispartof: GENETICS IN MEDICINE vol:23 issue:10 pages:1952-1960 ispartof: location:United States status: published

Intestinal parasitic infections affect more than 2 billion people throughout the world with disproportionately high prevalence rates in Low- and Middle-Income Countries (LMICs) (Herricks et al., 2017). Multicellular and highly complex parasites such as Ascaris, hook worm, Trichuris, Enterobius and Schistosoma, as well as unicellular organisms including Entamoeba, Giardia, Toxoplasma, Cyclospora, and Cryptosporidium are among major pathogens that contribute to the global intestinal parasitic disease burden.\ud \ud Parasites can cause persistent infection due to their ability to resist immune-mediated expulsion by modulating the host's immune response (McSorley and Maizels, 2012; Wammes et al., 2014; Chabé et al., 2017; Burrows et al., 2019; Ryan et al., 2020). There is a complex interaction between parasites and human microbiota which can triangulate with host's immune homeostasis and host responses to bystander antigens, vaccines or other unrelated diseases, both infectious and non-communicable diseases (McSorley and Maizels, 2012; Wammes et al., 2014). Recently, the world has grappled with an unprecedented pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19) (WHO, 2020). The pathogenesis of severe disease in COVID-19 has been linked to the phenomenon of immune hyperactivation (Sinha et al., 2020; Tay et al., 2020). Here, we propose that the interplay between intestinal parasites and microbiome may have a potential direct or indirect effects on the pathogenesis of SARS-CoV-2 infection, in particular in the context of LMICs.

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.1668F is a founder variant among Ashkenazi Jews (allele frequency of -.2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.

Background: Clinicians need to rapidly and reliably diagnose coronavirus disease 2019 (COVID-19) for proper risk stratification, isolation strategies, and treatment decisions.Purpose: To assess the real-life performance of radiologist emergency department chest CT interpretation for diagnosing COVID-19 during the acute phase of the pandemic, using the COVID-19 Reporting and Data System (CO-RADS).Materials and Methods: This retrospective multicenter study included consecutive patients who presented to emergency departments in six medical centers between March and April 2020 with moderate to severe upper respiratory symptoms suspicious for COVID-19. As part of clinical practice, chest CT scans were obtained for primary work-up and scored using the five-point CO-RADS scheme for suspicion of COVID-19. CT was compared with severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction (RT-PCR) assay and a clinical reference standard established by a multidisciplinary group of clinicians based on RT-PCR, COVID-19 contact history, oxygen therapy, timing of RT-PCR testing, and likely alternative diagnosis. Performance of CT was estimated using area under the receiver operating characteristic curve (AUC) analysis and diagnostic odds ratios against both reference standards. Subgroup analysis was performed on the basis of symptom duration grouped presentations of less than 48 hours, 48 hours through 7 days, and more than 7 days.Results: A total of 1070 patients (median age, 66 years; interquartile range, 54-75 years; 626 men) were included, of whom 536 (50%) had a positive RT-PCR result and 137 (13%) of whom were considered to have a possible or probable COVID-19 diagnosis based on the clinical reference standard. Chest CT yielded an AUC of 0.87 (95% CI: 0.84, 0.89) compared with RT-PCR and 0.87(95% CI: 0.85, 0.89) compared with the clinical reference standard. A CO-RADS score of 4 or greater yielded an odds ratio of 25.9 (95% CI: 18.7, 35.9) for a COVID-19 diagnosis with RT-PCR and an odds ratio of 30.6 (95% CI: 21.1, 44.4) with the clinical reference standard. For symptom duration of less than 48 hours, the AUC fell to 0.71 (95% CI: 0.62, 0.80; P =.001).Conclusion: Chest CT analysis using the coronavirus disease 2019 (COVID-19) Reporting and Data System enables rapid and reliable diagnosis of COVID-19, particularly when symptom duration is greater than 48 hours. (C) RSNA, 2020

ObjectivesTelephone consultations are frequently used in the outpatient setting in order to avoid unnecessary travel and to reduce hospital visit-related costs for patients. However, they are limited by the absence of non-verbal communication in contrast to video consultation. Little is known considering the possible advantages of using video consultation in comparison to telephone consultation according to both patients and healthcare providers.MethodsPatients with colorectal diseases were asked to choose between a telephone consultation or a video consultation for their next appointment at the outpatient clinic of a tertiary referral centre. Willingness to use video consultation, value of non-verbal communication, patient satisfaction, provider satisfaction and user friendliness of the video connection technology were measured using questionnaires.ResultsNone of the included patients ever had a video consultation before with a healthcare provider. Nonetheless, 22/50 preferred a video consultation over a telephone consultation. Patients who preferred a video consultation underlined the benefits of providing visual feedback to both patients and healthcare providers. Moreover, healthcare providers felt they were better able to assess the patients’ healthcare condition.ConclusionFor patients who value both verbal and non-verbal interaction and feel comfortable with the use of video consultation, video consultation is the preferred contact modality. Shared decision making should be used to choose the preferred interaction modality. For patients with low digital skills, support might be needed or video consultation may not be the preferred choice.

Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370. These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.

Background COVID-19 pandemic presented an unexpected challenge for the surgical community in general and Minimally Invasive Surgery (MIS) specialists in particular. This document aims to summarize recent evidence and experts’ opinion and formulate recommendations to guide the surgical community on how to best organize the recovery plan for surgical activity across different sub-specialities after the COVID-19 pandemic. Methods Recommendations were developed through a Delphi process for establishment of expert consensus. Domain topics were formulated and subsequently subdivided into questions pertinent to different surgical specialities following the COVID-19 crisis. Sixty-five experts from 24 countries, representing the entire EAES board, were invited. Fifty clinicians and six engineers accepted the invitation and drafted statements based on specific key questions. Anonymous voting on the statements was performed until consensus was achieved, defined by at least 70% agreement. Results A total of 92 consensus statements were formulated with regard to safe resumption of surgery across eight domains, addressing general surgery, upper GI, lower GI, bariatrics, endocrine, HPB, abdominal wall and technology/research. The statements addressed elective and emergency services across all subspecialties with specific attention to the role of MIS during the recovery plan. Eighty-four of the statements were approved during the first round of Delphi voting (91.3%) and another 8 during the following round after substantial modification, resulting in a 100% consensus. Conclusion The recommendations formulated by the EAES board establish a framework for resumption of surgery following COVID-19 pandemic with particular focus on the role of MIS across surgical specialities. The statements have the potential for wide application in the clinical setting, education activities and research work across different healthcare systems.

Introduction: Congenital atrioventricular block (CAVB) is a rare disorder with a significant morbidity and mortality. Consensus regarding the prescription and efficacy of prenatal corticosteroids is lacking. This nationwide study was initiated to evaluate the effects of prenatal treatment with corticosteroids on the outcome of CAVB in The Netherlands.Methods: All fetuses identified with isolated congenital AVB-II degrees or AVB-III degrees in any of the eight academic fetal heart centers of The Netherlands between 2003 and 2013 were included and reviewed.Results: Fifty-six fetuses were included. Fourteen (25%) fetuses were treated with dexamethasone. We found no differences between the steroid-treated and untreated cases regarding in utero progression of the AVB (63% vs 67% respectively), survival to birth (86% vs 84%), pacemaker implantations (74% vs 58%) or long-term dilated cardiomyopathy (13% vs 17%). Steroid treated fetuses demonstrated more in utero growth restriction (38% vs 11%).Conclusion: No benefit from prenatal corticosteroid treatment was demonstrated for fetuses with isolated CAVB in this study. However, we found negative side effects. Our data provide no evidence to support the routine administration of corticosteroids for the treatment of fetal CAVB. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Little is known about the epidemiology of HCV in Suriname, a former Dutch colony in South America. To study the prevalence, determinants and genetic diversity of HCV, a one-month survey was conducted at the only Emergency Department in the capital Paramaribo. Participants (>= 18 years) completed an interviewer-led standardized HCV risk-factor questionnaire, were tested for HCV-antibodies, and if positive also for HCV RNA. The overall HCV prevalence was 1.0% (22/2128 participants; 95%CI 0.7-1.5). Male sex (OR=4.11; 95%CI 1.30-13.01), older age (OR=1.06 per year increase; 95%CI 1.04-1.09), Javanese ethnicity (OR=7.84; 95%CI 3.25-18.89) and cosmetic tattooing (OR=31.7; 95%CI 3.25-323.87) were independently associated with HCV-infection. Phylogenetic analysis revealed six distinct HCV subtypes, all HCV-geno-type 2 (HCV-2): subtype 2f (also circulating in Indonesia) plus five yet unassigned HCV-2 subtypes exclusively linked to Suriname. (C) 2016 Elsevier Inc. All rights reserved

IntroductionMany low-income and middle-income countries (LMIC) suffer from a double burden of infectious diseases (ID) and non-communicable diseases (NCD). Previous research suggests that a high rate of gender inequality is associated with a higher ID and NCD burden in LMIC, but it is unknown whether gender inequality is also associated with a double burden of disease. In this ecological study, we explored the association between gender inequality and the double burden of disease in LMIC.MethodsFor 108 LMIC, we retrieved the Gender Inequality Index (GII, scale 0–1) and calculated the double burden of disease, based on disability-adjusted life-years for a selection of relevant ID and NCD, using WHO data. We performed logistic regression analysis to study the association between gender inequality and the double burden of disease for the total population, and stratified for men and women. We adjusted for income, political stability, type of labour, urbanisation, government health expenditure, health infrastructure and unemployment. Additionally, we conducted linear regression models for the ID and NCD separately.ResultsThe GII ranged from 0.13 to 0.83. A total of 37 LMIC had a double burden of disease. Overall, the adjusted OR for double burden of disease was 1.05 per 0.01 increase of GII (95% CI 0.99 to 1.10, p=0.10). For women, there was a borderline significant positive association between gender inequality and double burden of disease (OR 1.05, 95% CI 1.00 to 1.11, p=0.06), while there was no association in men (OR 0.99, 95% CI 0.95 to 1.04, p=0.75).ConclusionWe found patterns directing towards a positive association between gender inequality and double burden of disease, overall and in women. This finding suggests the need for more attention for structural factors underlying gender inequality to potentially reduce the double burden of disease.

Heavy menstrual bleeding (HMB) can negatively influence physical activity, work productivity, and sexual life and therefore has a major impact on women's quality of life (QoL). The National Institute for Health and Care Excellence guidelines recommend the levonorgestrel-releasing intrauterine system (LNG-IUS) as the treatment of first choice for HMB. Surgical treatments for treating HMB in women without future pregnancy wish include endometrial ablation (EA) and hysterectomy. Because of potentially biased studies and conflicting results on bleeding scores, satisfaction, and reintervention rate, there is no consensus on the efficacy of LNG-IUS versus EA. This multicenter, randomized controlled, noninferiority trial aimed to compare the effectiveness of the LNG-IUS system with EA in women with HMB. This study was performed between 2012 and 2016 in 26 hospitals in the Netherlands. Women were considered eligible if they had a diagnosed HMB with a Pictorial Blood Loss Assessment Chart (PBAC) score exceeding 150 points, were older than 34 years, had no pregnancy wish, and had no abnormal cervix cytology in the past 5 years. Participants were randomized in a 1:1 ratio to either the LNG-IUS or EA cohort. The LNG-IUS cohort had implantation of the device containing a total of 52 mg of levonorgestrel, releasing 20 μg/d. The EA intervention was performed with a bipolar radiofrequency device either in the office under local anesthetics or in the operating room under general or spinal anesthesia. The primary study outcome was menstrual blood loss at 24 months after randomization in PBAC, measured by participants through standardized questionnaires. Participants completed questionnaires before treatment and at 3, 6, 12, and 24 months after randomization. The primary analysis was an intention-to-treat analysis with a hypothesis that LNG-IUS would be noninferior to EA. Noninferiority of the LNG-IUS protocol would be established if the upper limit of the 95% confidence interval (CI) for the difference in PBAC score did not exceed the predetermined noninferiority margin of 25 points with P < 0.05. A total of 270 participants were randomized to initial treatment with LNG-IUS (n = 132) or treatment with EA (n = 138) between April 2012 and January 2016. A total of 247 participants (91%) reported PBAC scores at 24 months. The mean PBAC score was 64.8 in the LNG-IUS group compared with 14.2 in the EA group (mean difference, 50.5; 95% CI, 4.3-96.7). Noninferiority of LNG-IUS could not be demonstrated (noninferiority, P = 0.87). At 3 months of follow-up, 60% of women in the LNG-IUS group had reached a PBAC score of less than 75 points compared with 83% of women in the EA group (relative risk, 0.72; 95% CI, 0.59-0.87). The LNG-IUS was removed in 49 women (39%), and those in the LNG-IUS cohort were more likely to receive a surgical or drug reintervention within 24 months compared with women in the EA group (35% vs 20%; relative risk, 1.77; 95% CI, 1.17-2.68). There was no statistically significant difference in participant satisfaction and QoL between the cohorts. This study found that both the LNG-IUS and EA protocols for HMB led to a large decrease in menstrual blood loss, with LNG-IUS resulting in an increased risk of needing additional treatment and EA achieving a greater decrease in blood loss, with comparable QoL and satisfaction scores. Noninferiority of LNG-IUS compared with EA could not be demonstrated.

To investigate which factors are experienced as facilitators of or barriers to return to work (RTW), or as solutions to RTW-problems, by patients with acquired brain injury (ABI) and by employers.Qualitative study.Ten patients with ABI and seven employers participated in semi-structured interviews. Patients and employers were unrelated. Transcripts were open coded. Factors perceived to be facilitators, barriers, or solutions to RTW-problems were grouped on a thematic basis.Both patients and employers distinguished patient-related and work-related facilitators. When questioned about barriers, both patients and employers emphasized the importance of work-related factors such as sensory overload at the workplace and condition-related factors such as fatigue. Patients regarded poor guidance and support as barriers, but employers did not. Employers and patients suggested that solutions to RTW-problems were work-related, if necessary backed up by professional supervision. Patients also mentioned the need for understanding and acceptance of the limitations resulting from ABI.Both patients and employers mentioned work-related and patient-related facilitators, work-related and condition-related barriers, and work-related solutions to RTW-problems. Patients mentioned lack of guidance and support as barriers, and stressed the need for understanding and acceptance of the limitations resulting from ABI in any RTW-solution. Implications for rehabilitation •Patients and employers are important stakeholders in the return to work (RTW) process of a patient with acquired brain injury (ABI) •Professionals in rehabilitation practice, occupational and insurance physicians need to help patients and employers to realize RTW •Professionals have to be aware of the perspectives of patients and employers regarding RTW, such as: ^Little understanding of limitations resulting from ABI ^Work-related aspects hindering RTW, such as sensory overload and high work pressure ^Condition-related barriers to RTW such as (invisible) cognitive limitations and fatigue ^Need for professional assistance during the RTW process.

Background The use of Fall-Risk-Increasing-Drugs (FRIDs) has been associated with increased risk of falls and associated injuries. This study investigates the effect of withdrawal of FRIDs versus ‘care as usual’ on health-related quality of life (HRQoL), costs, and cost-utility in community-dwelling older fallers. Methods In a prospective multicenter randomized controlled trial FRIDs assessment combined with FRIDs-withdrawal or modification was compared with ‘care as usual’ in older persons, who visited the emergency department after experiencing a fall. For the calculation of costs the direct medical costs (intramural and extramural) and indirect costs (travel costs) were collected for a 12 month period. HRQoL was measured at baseline and at 12 months follow-up using the EuroQol-5D and Short Form-12 version 2. The change in EuroQol-5D and Short Form-12 scores over 12 months follow-up within the control and intervention groups was compared using the Wilcoxon Signed Rank test for continuous variables and the McNemar test for dichotomous variables. The change in scores between the control and intervention groups were compared using a two-way analysis of variance. Results We included 612 older persons who visited an emergency department because of a fall. The mean cost of the FRIDs intervention was €120 per patient. The total fall-related healthcare costs (without the intervention costs) did not differ significantly between the intervention group and the control group (€2204 versus €2285). However, the withdrawal of FRIDs reduced medication costs with a mean of €38 per participant. Furthermore, the control group had a greater decline in EuroQol-5D utility score during the 12-months follow-up than the intervention group (p = 0.02). The change in the Short Form-12 Physical Component Summary and Mental Component Summary scores did not differ significantly between the two groups. Conclusions Withdrawal of FRID’s in older persons who visited an emergency department due to a fall, did not lead to reduction of total health-care costs. However, the withdrawal of FRIDs reduced medication costs with a mean of €38 per participant in combination with less decline in HRQoL is an important result. Trial registration The trial is registered in the Netherlands Trial Register (NTR1593 – October 1st 2008). Electronic supplementary material The online version of this article (doi:10.1186/s12877-016-0354-7) contains supplementary material, which is available to authorized users.

Aim: To evaluate whether intestinal microbiota predicts the development of new-onset urinary tract infections (UTIs) in postmenopausal women with prior recurrent UTIs (rUTIs). Patients & methods: Fecal samples (n = 40) originated from women with rUTI who received 12 months’ prophylaxis of either trimethoprim–sulfamethoxazole (TMP–SMX) or lactobacilli. Microbial composition was assessed by 16S rRNA pyrosequencing. Results: At baseline, fecal microbiota of women with zero and more than or equal to four UTIs during follow-up showed no significant differences. Only TMP–SMX prophylaxis resulted in reduced microbial diversity. Microbial structure of two samples from the same woman showed limited relatedness. Conclusion: In postmenopausal women with rUTI, the intestinal microbiota was not predictive for new-onset UTIs. Only TMP–SMX, and not lactobacilli, prophylaxis had effects on the microbial composition. Data in ENA:PRJEB13868.

Item does not contain fulltext STUDY QUESTION: Does embryo culture medium influence pregnancy and perinatal outcome in IVF? SUMMARY ANSWER: Embryo culture media used in IVF affect treatment efficacy and the birthweight of newborns. WHAT IS KNOWN ALREADY: A wide variety of culture media for human preimplantation embryos in IVF/ICSI treatments currently exists. It is unknown which medium is best in terms of clinical outcomes. Furthermore, it has been suggested that the culture medium used for the in vitro culture of embryos affects birthweight, but this has never been demonstrated by large randomized trials. STUDY DESIGN, SIZE, DURATION: We conducted a multicenter, double-blind RCT comparing the use of HTF and G5 embryo culture media in IVF. Between July 2010 and May 2012, 836 couples (419 in the HTF group and 417 in the G5 group) were included. The allocated medium (1:1 allocation) was used in all treatment cycles a couple received within 1 year after randomization, including possible transfers with frozen-thawed embryos. The primary outcome was live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples that were scheduled for an IVF or an ICSI treatment at one of the six participating centers in the Netherlands or their affiliated clinics. MAIN RESULTS AND THE ROLE OF CHANCE: The live birth rate was higher, albeit nonsignificantly, in couples assigned to G5 than in couples assigned to HTF (44.1% (184/417) versus 37.9% (159/419); RR: 1.2; 95% confidence interval (CI): 0.99-1.37; P = 0.08). Number of utilizable embryos per cycle (2.8 +/- 2.3 versus 2.3 +/- 1.8; P < 0.001), implantation rate after fresh embryo transfer (20.2 versus 15.3%; P < 0.001) and clinical pregnancy rate (47.7 versus 40.1%; RR: 1.2; 95% CI: 1.02-1.39; P = 0.03) were significantly higher for couples assigned to G5 compared with those assigned to HTF. Of the 383 live born children in this trial, birthweight data from 380 children (300 singletons (G5: 163, HTF: 137) and 80 twin children (G5: 38, HTF: 42)) were retrieved. Birthweight was significantly lower in the G5 group compared with the HTF group, with a mean difference of 158 g (95% CI: 42-275 g; P = 0.008). More singletons were born preterm in the G5 group (8.6% (14/163) versus 2.2% (3/137), but singleton birthweight adjusted for gestational age and gender (z-score) was also lower in the G5 than in the HTF group (-0.13 +/- 0.08 versus 0.17 +/- 0.08; P = 0.008). LIMITATIONS, REASONS FOR CAUTION: This study was powered to detect a 10% difference in live births while a smaller difference could still be clinically relevant. The effect of other culture media on perinatal outcome remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: Embryo culture media used in IVF affect not only treatment efficacy but also perinatal outcome. This suggests that the millions of human embryos that are cultured in vitro each year are sensitive to their environment. These findings should lead to increased awareness, mechanistic studies and legislative adaptations to protect IVF offspring during the first few days of their existence. STUDY FUNDING/COMPETING INTERESTS: This project was partly funded by The NutsOhra foundation (Grant 1203-061) and March of Dimes (Grant 6-FY13-153). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NTR1979 (Netherlands Trial Registry). TRIAL REGISTRATION DATE: 1 September 2009. DATE OF FIRST PATIENT'S ENROLMENT: 18 July 2010.

Objective To examine the accuracy and timing of diagnosis of fetal cleft lip with or without cleft palate (CL +/- P) in the years following the introduction of a national screening program, and to assess the completeness and accuracy of information in The Netherlands Perinatal Registry.Methods A list was obtained of cases with a prenatal or postnatal diagnosis of CL +/- P from two fetal medicine units between 2008 and 2012. All cases of CL +/- P were included irrespective of the presence or absence of additional anomalies. Cases were included if the estimated date of delivery was between 1 January 2008 and 31 December 2012.Results During the study period, 330 cases of CL +/- P were identified, with a prevalence of 15 per 10 000 pregnancies. The number of cases that were detected before 24 weeks' gestation increased during the study period, while the rate of termination of pregnancy did not change significantly (P=0.511). CL +/- P was isolated in 217 (66%) cases and karyotype was abnormal in 69 (21%) cases. In 5% of the cases in which CL +/- P seemed to be isolated during the 18-23-week anomaly scan, postnatal array comparative genomic hybridization (array-CGH) revealed an abnormal karyotype and 50% of these cases had major additional anomalies. Examination of data from The Netherlands Perinatal Registry demonstrated that in 37% of cases CL +/- P was not recorded in the pregnancy records.Conclusion CL +/- P is increasingly being diagnosed prenatally, without a significant effect on the rate of pregnancy termination. Further improvement in the diagnostic accuracy may be achieved by advocating prenatal array-CGH to reduce the frequency of unexpected anomalies being diagnosed after birth. It is important that healthcare providers register accurately the presence or absence of anomalies in the birth records to ensure that, in the future, data from The Netherlands Perinatal Registry can be relied upon to monitor prevalence. Copyright (C) 2015 ISUOG. Published by John Wiley & Sons Ltd.

Previously, we demonstrated that cognitive behavior therapy for ultra-high risk (called CBTuhr) halved the incidence of psychosis over an 18-month period. Follow-up data from the same study are used to evaluate the longer-term effects at 4 years post-baseline.The Dutch Early Detection and Intervention Evaluation study was a randomized controlled trial of 196 UHR patients comparing CBTuhr with treatment-as-usual (TAU) for comorbid disorders with TAU only. Of the original 196 patients, 113 consented to a 4-year follow-up (57.7%; CBTuhr = 56 vs TAU = 57). Over the study period, psychosis incidence, remission from UHR status, and the effects of transition to psychosis were evaluated.The number of participants in the CBTuhr group making the transition to psychosis increased from 10 at 18-month follow-up to 12 at 4-year follow-up whereas it did not change in the TAU group (n = 22); this still represents a clinically important (incidence rate ratio [IRR] = 12/22 = 0.55) and significant effect (F(1,5) = 8.09, P = .03), favoring CBTuhr. The odds ratio of CBTuhr compared to TAU was 0.44 (95% CI: 0.24-0.82) and the number needed to treat was 8. Moreover, significantly more patients remitted from their UHR status in the CBTuhr group (76.3%) compared with the TAU group (58.7%) [t(120) = 2.08, P = .04]. Importantly, transition to psychosis was associated with more severe psychopathology and social functioning at 4-year follow-up.CBTuhr to prevent a first episode of psychosis in persons at UHR of developing psychosis is still effective at 4-year follow-up. Our data also show that individuals meeting the formal criteria of a psychotic disorder have worse functional and social outcomes compared with non-transitioned cases.The trial is registered at Current Controlled Trials as trial number ISRCTN21353122 (http://controlled-trials.com/ISRCTN21353122/gaag).? The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

BACKGROUND Dexmedetomidine possesses anxiolytic and hypnotic properties without respiratory side-effects, making it theoretically an ideal sedative agent for endoscopic procedures. OBJECTIVE We aimed to compare satisfaction and safety among outpatients receiving sedation with dexmedetomidine or propofol for endoscopic oesophageal procedures. DESIGN A randomised controlled study. SETTING Endoscopic intervention suite at the Academic Medical Centre in Amsterdam, Netherlands. PARTICIPANTS Patients aged at least 18 years, and American Society of Anesthesiologists' physical status 1 to 3. INTERVENTION Total 63 patients were randomised to receive either dexmedetomidine (D) or propofol (P). Pain was treated with alfentanil in both groups. MAIN OUTCOME MEASURES The primary outcomes were patients' and endoscopists' satisfaction levels measured by validated questionnaires (1 = very dissatisfied; 7 = highly satisfied). A secondary outcome was safety, determined by blood pressure, heart rate and oxygen saturation during and after the procedure, and respiratory rate and noninvasive cardiac output during the procedure. RESULTS Satisfaction of patients [median (IQR); group D, 5.0 (3.75 to 5.75) vs. group P, 6.25 (5.3 to 6.5)] and satisfaction of gastroenterologists [group D, 5.0 (4.4 to 5.8) vs. group P, 6.0 (5.4 to 6.0)] were lower in group D (both P

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor β (TGF-β)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [ p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C [p.Glu70Gln], c.299T>A [p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.

Background The current political agenda aims to promote active environments and physical activity while commuting to work, but research on it has provided mixed results. This study examines whether the proximity of green space and people’s residence in different travel-related urban zones contributes to commuting physical activity. Methods Population-based cross-sectional health examination survey, Health 2011 study, and geographical information system (GIS) data were utilized. The GIS data on green space and travel-related urban zones were linked to the individuals of the Health 2011 study, based on their home geocoordinates. Commuting physical activity was self-reported. Logistic regression models were applied, and age, gender, education, leisure-time and occupational physical activity were adjusted. Analyses were limited to those of working age, living in the core-urban areas of Finland and having completed information on commuting physical activity (n = 2 098). Results Home location in a pedestrian zone of a main centre (odds ratio = 1.63; 95 % confidence interval = 1.06–2.51) or a pedestrian zone of a sub-centre (2.03; 1.09–3.80) and higher proportion of cycling and pedestrian networks (3.28; 1.71–6.31) contributed to higher levels of commuting physical activity. The contribution remained after adjusting for all the environmental attributes and individuals. Based on interaction analyses, women living in a public transport zone were almost two times more likely to be physically active while commuting compared to men. A high proportion of recreational green space contributed negatively to the levels of commuting physical activity (0.73; 0.57–0.94) after adjusting for several background factors. Based on interaction analyses, individuals aged from 44 to 54 years and living in sub-centres, men living in pedestrian zones of sub-centres, and those individuals who are physically inactive during leisure-time were less likely to be physically active while commuting. Conclusions Good pedestrian and cycling infrastructure may play an important role in promoting commuting physical activity among the employed population, regardless of educational background, leisure-time and occupational physical activity. Close proximity to green space and a high proportion of green space near the home may not be sufficient to initiate commuting physical activity in Finland, where homes surrounded by green areas are often situated in car-oriented zones far from work places.

Objective:Cognitive behaviour therapy (CBT) reduces fatigue and disability in chronic fatigue syndrome (CFS). However, outcomes vary between studies, possibly because of differences in patient characteristics, treatment protocols, diagnostic criteria and outcome measures. The objective was to compare outcomes after CBT in tertiary treatment centres in the Netherlands (NL) and the United Kingdom (UK), using different treatment protocols but identical outcome measures, while controlling for differences in patient characteristics and diagnostic criteria.Methods:Consecutively referred CFS patients who received CBT were included (NL: n = 293, UK: n = 163). Uncontrolled effect sizes for improvement in fatigue (Chalder Fatigue Questionnaire), physical functioning (SF-36 physical functioning subscale) and social functioning (Work and Social Adjustment Scale) were compared. Multiple regression analysis was used to examine whether patient differences explained outcome differences between centres.Results:Effect sizes differed between centres for fatigue (Cohen's D NL = 1.74, 95% CI = 1.52–1.95; UK = 0.99, CI = 0.73–1.25), physical functioning (NL = 0.99, CI = 0.81–1.18; UK = 0.33, CI = 0.08–0.58) and social functioning (NL = 1.47, CI = 1.26–1.69; UK = 0.61, CI = 0.35–0.86). Patients in the UK had worse physical functioning at baseline and there were minor demographic differences. These could not explain differences in centre outcome.Conclusion:Effectiveness of CBT differed between treatment centres. Differences in treatment protocols may explain this and should be investigated to help further improve outcomes.

ContextThyroid dysfunction is thought to be associated with stillbirth. Therefore, thyroid function is often recommended in the diagnostic investigations for stillbirth.ObjectiveWe aimed to evaluate the added value of thyroid function testing in the diagnostic investigations for stillbirth.Design and patientsA nationwide multicentre prospective cohort study in 1025 women who suffered stillbirth >20 weeks of gestation performed between 2002 and 2008. In each woman, an extensive diagnostic work-up was performed, including placental examination and autopsy. TSH and FT4 values below the 25th percentile or above the 975th percentile according local laboratory reference values were regarded as abnormal. Women with a history of thyroid disease were evaluated separately.Main outcome measuresThyroid function abnormalities in women with stillbirth.ResultsOf 1025 included women, 21 had a history of thyroid disease (2%). In the 875 with TSH and FT4 results and no history of thyroid disease, 10% had hypothyroxinemia, 46% subclinical hypothyroidism, 16% overt hypothyroidism and 15% subclinical hyperthyroidism. Women with a subclinical hyperthyroidism more often had a foetal death caused by foetal hydrops: 23% vs 29% (adjusted OR 103, 95% CI 25-42).ConclusionsWomen with a stillbirth had a slightly higher prevalence of overt hypothyroidism, subclinical hypothyroidism and hypothyroxinaemia compared to previous studies on thyroid dysfunction in pregnant women. Given the absence of a strong associations with the cause of stillbirth, and no demonstrated beneficial effects of treating thyroid dysfunction in these women, routine screening after stillbirth is not justified.

Background Higher Tobacco Control Scale (TCS) scores, in the early 2000s were associated with higher smoking cessation rates across Europe, both among lower and higher educated people. We aimed to assess if this association held in recent years. Methods Repeated cross-sectional Eurobarometer surveys were used, in 27 European countries from 2006 to 2012 (study sample = 73,617 adults). We used multilevel regression to model associations between the TCS (ranging from 0 to 100, quantifying: tobacco price, smoke-free laws, mass-media campaigns, advertising bans, warning labels, and cessation support) and both smoking cessation and cigarettes smoked per day. We modelled associations according to respondents’ education and occupation, with adjustment for age, sex, and survey-wave. Results We found no association between the TCS and smoking cessation for lower or middle educated respondents, but we did find an association for higher educated respondents (OR: 1.13, 95%CI: 1.08 to 1.19). For smoking intensity, we observed no associations with the TCS for lower educated respondents (beta: 0.04, 95%CI: −0.33 to 0.41) but we did observe significant associations for middle (beta: −0.25, 95%CI: −0.47 to −0.03) and higher educated respondents (beta: −0.27, 95%CI: −0.55 to −0.01). Associations were observed for both manual and non-manual classes, but not for those not working for pay. Of the TCS domains, none were associated with smoking cessation for lower educated respondents, but five were for higher educated respondents. Conclusions Associations between tobacco control policies and smoking cessation were found mostly among higher socioeconomic groups. This underlines the need for specific tobacco control policies that explicitly focus on reaching low socio-economic groups.

Objectives: To describe the grading of recommendations assessment, development and evaluation (GRADE) interactive evidence to decision (EtD) frameworks for tests and test strategies for clinical, public health, or coverage decisions. Study Design and Setting: As part of the GRADE Working Group's DECIDE project, we conducted workshops, user testing with systematic review authors, guideline developers and other decision makers, and piloted versions of the EtD framework. Results: EtD frameworks for tests share the structure, explicitness, and transparency of other EtD frameworks. They require specifying the purpose of the test, linked or related management, and the key outcomes of concern for different test results and subsequent management. The EtD criteria address test accuracy and assessments of the certainty of the additional evidence necessary for decision making. When there is no direct evidence of test effects on patient-important outcomes, formal or informal modeling is needed to estimate effects. We describe the EtD criteria based on examples developed with GRADEpro (www.gradepro.org), GRADE's software that also allows development and dissemination of interactive summary of findings tables. Conclusion: EtD frameworks for developing recommendations and making decisions about tests lay out the sequential steps in reviewing and assessing the different types of evidence that need to be linked. (C) 2016 Elsevier Inc. All rights reserved.

Supporting pregnant women to make informed choices about Down syndrome screening is widely endorsed. We reviewed the literature on: (a) the association between socioeconomic position and informed choices and decision-making about Down syndrome screening, and (b) the possible mediating variables (e.g., health literacy, numeracy skills, behavioral and communication variables) that might explain the relationship. EMBASE, MEDLINE, PubMed, CINAHL, and PsycINFO were searched from January 1999 to September 2014. The methodological quality of studies was determined by predefined criteria regarding the research aims, study design, study population and setting, measurement tools, and statistical analysis. A total of 33 studies met the inclusion criteria. Women from lower socioeconomic groups experience greater difficulties making informed choices about Down syndrome screening compared to women from higher socioeconomic groups. Most studies focus on individual dimensions of informed decision-making rather than assessing elements in conjunction with one another. Few studies have explored why there are socioeconomic differences in women's ability to make informed screening decisions. Future work is needed to identify mediating variables in this pathway. Systematic evidence-based intervention development to improve communication, understanding, and decision-making about Down syndrome screening is needed to ensure that women have an equal opportunity to make an informed choice about screening regardless of their socioeconomic position.

Purpose Dexamethasone is a key component in the treatment of pediatric acute lymphoblastic leukemia (ALL), but can induce serious adverse effects. Recent studies have led to the hypothesis that neuropsychological adverse effects may be a result of cortisol depletion of the cerebral mineralocorticoid receptors. We examined whether including a physiologic dose of hydrocortisone in dexamethasone treatment can reduce neuropsychologic and metabolic adverse effects in children with ALL. Patients and Methods We performed a multicenter, double-blind, randomized controlled trial with a crossover design. Of 116 potentially eligible patients (age 3 to 16 years), 50 were enrolled and were treated with two consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols. Patients were randomly assigned to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m2/d) during both dexamethasone courses. Primary outcome measure was parent-reported Strength and Difficulties Questionnaire in Dutch, which assesses psychosocial problems. Other end points included questionnaires, neuropsychological tests, and metabolic parameters. Results Of 48 patients who completed both courses, hydrocortisone had no significant effect on outcome; however, a more detailed analysis revealed that in 16 patients who developed clinically relevant psychosocial adverse effects, addition of hydrocortisone substantially reduced their Strength and Difficulties Questionnaire in Dutch scores in the following domains: total difficulties, emotional symptoms, conduct problems, and impact of difficulties. Moreover, in nine patients who developed clinically relevant, sleep-related difficulties, addition of hydrocortisone reduced total sleeping problems and disorders of initiating and maintaining sleep. In contrast, hydrocortisone had no effect on metabolic parameters. Conclusion Our results suggest that adding a physiologic dose of hydrocortisone to dexamethasone treatment can reduce the occurrence of serious neuropsychological adverse effects and sleep-related difficulties in pediatric patients with ALL.

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Early recognition of the pathogen and subsequent innate immune response play a vital role in disease susceptibility and outcome. Genetic variations in innate immune genes can alter the immune response and influence susceptibility and outcome of meningitis disease. Here we conducted a sequencing study of coding regions from 46 innate immune genes in 435 pneumococcal meningitis patients and 416 controls, to determine the role of genetic variation on pneumococcal meningitis susceptibility and disease outcome. Strongest signals for susceptibility were rs56078309 CXCL1 (p = 4.8e − 04) and rs2008521 in CARD8 (p = 6.1e − 04). For meningitis outcome the rs2067085 in NOD2 (p = 5.1e − 04) and rs4251552 of IRAK4 were the strongest associations with unfavorable outcome (p = 6.7e − 04). Haplotype analysis showed a haplotype block, determined by IRAK4 rs4251552, significantly associated with unfavorable outcome (p = 0.004). Cytokine measurements from cerebrospinal fluid showed that with the IRAK4 rs4251552 G risk allele had higher levels of IL-6 compared to individuals with A/A genotype (p = 0.04). We show that genetic variation within exons and flanking regions of 46 innate immunity genes does not yield significant association with pneumococcal meningitis. The strongest identified signal IRAK4 does imply a potential role of genetic variation in pneumococcal meningitis., Highlights • Exome variations of 46 innate immune genes show no association with pneumococcal meningitis susceptibility and outcome. • Variations that have previously been associated with invasive pneumococcal disease or meningitis could not be replicated. • Highest signals found were variations in CXCL1 and CARD8 for susceptibility and NOD2 and IRAK4 for outcome. • The IRAK4 rs4251552 variant shows a trend where patients with a G-allele have higher IL-6 levels in their liquor. The pneumococcus is the most common causative pathogen of bacterial meningitis. We investigated the association of genetic variation within the coding sequences and flanking intronic regions of 46 innate immunity genes. These genes are responsible for our first line of defense during invading pathogens. In a cohort of 435 pneumococcal meningitis patients and 416 controls we found that variation within CXCL1 and CARD8 were the strongest signals associated with pneumococcal meningitis susceptibility. For disease severity we identified variations in NOD2 and IRAK4 genes to be associated with outcome. These findings can help in the understanding and treatment of pneumococcal meningitis.

Preclinical studies have suggested that platelets influence the host response during sepsis. We sought to assess the association of admission thrombocytopenia with the presentation, outcome, and host response in patients with sepsis. Nine hundred thirty-one consecutive sepsis patients were stratified according to platelet counts (very low

Since the first successful live birth after in vitro fertilization (IVF) was reported in 1978, more than 5 million children have been born with the help of this and intracytoplasmic sperm injection (ICSI) procedures. However, only approximately 25% to 30% of cycles of IVF and ICSI lead to the birth of a child. The reasons for implantation failure are poorly understood. One major cause of implantation failure is abnormalities of the uterine cavity such as polyps, myoma, and adhesions. Hysteroscopy has been generally regarded as the standard procedure to detect these uterine abnormalities. It is thought to improve pregnancy rates in women scheduled for IVF by detection and surgical removal of uterine cavity abnormalities, dilatation of the cervical canal, or induction of inflammatory reactions in the endometriumby the procedure itself. Hysteroscopy is often performed routinely in infertile women scheduled for their first IVF cycle. However, there are no data from well-designed randomized controlled trials to support this practice. The inSIGHT trial is a pragmatic multicenter randomized clinical trial designed to determine whether routine hysteroscopy before the first IVF treatment cycle increases the live birth rate. The trial was conducted in 7 university hospitals and 15 large general hospitals in the Netherlands. Women eligible for the trial were infertile, scheduled to start their first IVF or ICSI treatment, had no previous hysteroscopy, and had a normal transvaginal ultrasound of the uterine cavity. Subjects were randomly assigned in a 1: 1 ratio to hysteroscopy with treatment of detected intracavitary abnormalities before starting IVF followed by IVF (hysteroscopy group) or to immediate start of IVF treatment (immediate IVF group). Web-based randomization was done with a variable block size to allocate patients to groups and was stratified by center. The doctors, outcome assessors, and participants were not masked to the assigned group. The primary study outcome was an ongoing pregnancy (detection of a fetal heartbeat at > 12weeks of gestation) within 18 months of randomization and a live birth. Analysis was done according to intention to treat. Between May 25, 2011, and August 27, 2013, 750 women were randomized: 373 to the hysteroscopy group and 377 to the immediate IVF group. A live birth occurred during the trial period in 209 (57%) of 369 women in the hysteroscopy group and 200 (54%) of 373 in the immediate IVF group; the relative riskwas 1.06, with a 95% confidence interval of 0.93 to 1.20; P = 0.41. These findings demonstrate that hysteroscopy does not improve live birth rates in infertile women scheduled for their first IVF cycle, who have a normal transvaginal ultrasound of the uterine cavity. Therefore, routine hysteroscopy should not be performed in women with a normal transvaginal ultrasound.

Objectives The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group has developed GRADE evidence profiles (EP) and summary of findings (SoF) tables to present evidence summaries in systematic reviews, clinical guidelines, and health technology assessments. Explanatory notes are used to explain choices and judgments in these summaries, for example, on rating of the quality of evidence. Study Design and Setting A systematic survey of the explanations in SoF tables in 132 randomly selected Cochrane Intervention reviews and in EPs of 10 guidelines. We analyzed the content of 1,291 explanations using a predefined list of criteria. Results Most explanations were used to describe or communicate results and to explain downgrading of the quality of evidence, in particular for risk of bias and imprecision. Addressing the source of baseline risk (observational data or control group risk) was often missing. For judgments about downgrading the quality of evidence, the percentage of informative explanations ranged between 41% (imprecision) and 79% (indirectness). Conclusion We found that by and large explanations were informative but detected several areas for improvement (e.g., source of baseline risk and judgments on imprecision). Guidance about explanatory footnotes and comments will be provided in the last article in this series.

We aimed to describe survival in European pediatric dialysis patients and compare the differential mortality risk between patients starting on hemodialysis (HD) and peritoneal dialysis (PD). Data for 6473 patients under 19 years of age or younger were extracted from the European Society of Pediatric Nephrology, the European Renal Association, and European Dialysis and Transplant Association Registry for 36 countries for the years 2000 through 2013. Hazard ratios (HRs) were adjusted for age at start of dialysis, sex, primary renal disease, and country. A secondary analysis was performed on a propensity score-matched (PSM) cohort. The overall 5-year survival rate in European children starting on dialysis was 89.5% (95% confidence interval [CI] 87.7%-91.0%). The mortality rate was 28.0 deaths per 1000 patient years overall. This was highest (36.0/1000) during the first year of dialysis and in the 0- to 5-year age group (49.4/1000). Cardiovascular events (18.3%) and infections (17.0%) were the main causes of death. Children selected to start on HD had an increased mortality risk compared with those on PD (adjusted HR 1.39, 95% CI 1.06-1.82, PSM HR 1.46, 95% CI 1.06-2.00), especially during the first year of dialysis (HD/PD adjusted HR 1.70, 95% CI 1.22-2.38, PSM HR 1.79, 95% CI 1.20-2.66), when starting at older than 5 years of age (HD/PD: adjusted HR 1.58, 95% CI 1.03-2.43, PSM HR 1.87, 95% CI 1.17-2.98) and when children have been seen by a nephrologist for only a short time before starting dialysis (HD/PD adjusted HR 6.55, 95% CI 2.35-18.28, PSM HR 2.93, 95% CI 1.04-8.23). Because unmeasured case-mix differences and selection bias may explain the higher mortality risk in the HD population, these results should be interpreted with caution.

Background Robotic partial nephrectomy (RPN) is established as a minimally invasive nephron-sparing technique with excellent perioperative and intermediate oncologic outcomes. However, long-term oncologic outcomes have not been reported to date. Objective To report long-term oncologic outcomes of RPN. Design, setting, and participants Consecutive patients undergoing RPN from June 2006 to March 2010 were selected from our prospective RPN database. Patients with benign tumors, prior ipsilateral PN, or prior radical nephrectomy and those with follow-up of Intervention Transperitoneal RPN. Outcomes measurements and statistical analysis Demographic, perioperative, and postoperative data were analyzed. Overall survival (OS), cancer-free survival (CFS), and cancer-specific survival (CSS) were evaluated using Kaplan-Meier survival analysis. Univariate logistic regression analysis for overall mortality was performed to evaluate the odds ratio (OR) for variables of interest. Results and limitations In total, 115 RPNs for RCC were performed in 110 patients. The mean age was 59.8±11.0 yr and the median age-adjusted Charlson comorbidity index (ACCI) was 4 (interquartile range [IQR] 3–5). The median tumor size was 2.6cm (IQR 2.0–3.7) and median RENAL score was 7 (IQR 6–9). Clear cell carcinoma was present in 67.8% of cases, and two cases (1.7%) had positive surgical margins. Glomerular filtration rate preservation was 87.8% (IQR 74.9–98.1), which translates to 19.1% chronic kidney disease upstaging. The median follow-up was 61.9 mo (IQR 50.9–71.4) and the 5-yr OS, CFS, and CSS were 91.1%, 97.8%, and 97.8%, respectively. On univariable logistic regression, ACCI was the only factor associated with a higher risk of overall mortality (OR 1.67, p =0.006). The retrospective design, the high surgical volume at our institution, and the potential selection bias with careful patient selection early in the RPN experience may limit the generalizability of our findings. Conclusions This is the first study confirming excellent long-term oncologic outcomes after RPN in a selected cohort of patients. Patient summary Robotic partial nephrectomy is a relatively recently developed treatment for renal cell carcinoma. This study confirms its safety and reports excellent long-term cancer control.

Treatment of adolescents with antidepressants may induce an increased risk for suicidality in this population. The activity of the amygdala during processing of emotional faces with functional Magnetic Resonance Imaging (fMRI) is a well-known measure of emotional dysregulation. Based upon data of our prematurely ended randomized clinical trial with fluoxetine (NTR3103) in anxious and or depressed girls (12–14 years of age) we calculated that with the found effect size of r = 0.66, compared to placebo, only 8 subjects are needed to demonstrate increased amygdala activity following 16 weeks of treatment with fluoxetine.

Background Previous evaluations have documented that studies evaluating the effectiveness of therapeutic interventions are not always reported, and that those with statistically significant results are published more rapidly than those without. This can lead to reporting bias in systematic reviews and other literature syntheses. We evaluated whether diagnostic accuracy studies that report promising results about the performance of medical tests are also published more rapidly. Methods We obtained all primary diagnostic accuracy studies included in meta-analyses of Medline-indexed systematic reviews that were published between September 2011 and January 2012. For each primary study, we extracted estimates of diagnostic accuracy (sensitivity, specificity, Youden’s index), the completion date of participant recruitment, and the publication date. We calculated the time from completion to publication and assessed associations with reported accuracy estimates. Results Forty-nine systematic reviews were identified, containing 92 meta-analyses and 924 unique primary studies, of which 756 could be included. Study completion dates were missing for 285 (38 %) of these. Median time from completion to publication in the remaining 471 studies was 24 months (IQR 16 to 35). Primary studies that reported higher estimates of sensitivity (Spearman’s rho = −0.14; p = 0.003), specificity (rho = −0.17; p

Background & Aims Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs after resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence. Methods We evaluated the efficacy of infliximab in preventing postoperative recurrence of CD in 297 patients at 104 sites worldwide from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary end point was clinical recurrence, defined as a composite outcome consisting of a CD Activity Index score >200 and a ≥70-point increase from baseline, and endoscopic recurrence (Rutgeerts score ≥i2, determined by a central reader) or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary end point. Results A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval: -1.3% to 15.5%; P =.097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared with the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% confidence interval: 18.6% to 40.2%; P

Aims: \ud \ud Despite major improvements in pharmacological and device treatments, heart failure remains a syndrome with high morbidity and mortality, poor quality of life, and high health-care costs. Given the extensive heterogeneity among patients with heart failure, substantial differences in the response to therapy can be expected. We hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure.\ud Methods: \ud \ud The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and/or symptoms of heart failure from 11 European countries, who were considered to be on suboptimal medical treatment. Another 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. The majority of patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and/or symptoms of heart failure at outpatient clinics. Approximately half of the patients were in New York Heart Association class III, and 7% vs 34% of patients of the index vs validation cohort had heart failure with preserved ejection fraction. According to study design, all patients used diuretics, but owing to the inclusion criteria of both cohorts, patients were not on optimal, evidence-based medical therapy. In the follow-up phase, uptitration to guideline-recommended doses was encouraged.\ud Conclusion: \ud \ud By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure.

Background: Current surgical and ablative treatment options for prostate cancer (PCa) may result in a high incidence of (temporary) incontinence, erectile dysfunction and/or bowel damage. These side effects are due to procedure related effects on adjacent structures including blood vessels, bowel, urethra and/or neurovascular bundle. Ablation with irreversible electroporation (IRE) has shown to be effective and safe in destroying PCa cells and also has the potential advantage of sparing surrounding tissue and vital structures, resulting in less impaired functional outcomes and maintaining men's quality of life. Methods/Design: In this randomized controlled trial (RCT) on IRE in localized PCa, 200 patients with organ-confined, unilateral (T1c-T2b) low- to intermediate-risk PCa (Gleason sum score 6 and 7) on transperineal template-mapping biopsies (TTMB) will be included. Patients will be randomized into focal or extended ablation of cancer foci with IRE. Oncological efficacy will be determined by multiparametric Magnetic Resonance Imaging, Contrast-Enhanced Ultrasound imaging if available, TTMP and Prostate Specific Antigen (PSA) follow-up. Patients will be evaluated up to 5 years on functional outcomes and quality of life with the use of standardized questionnaires. Discussion: There is critical need of larger, standardized RCTs evaluating long-term oncological and functional outcomes before introducing IRE and other focal therapy modalities as an accepted and safe therapeutic option for PCa. This RCT will provide important short- and long-term data and elucidates the differences between focal or extended ablation of localized, unilateral low- to intermediate-risk PCa with IRE. Trial registration: Clinicaltrials.gov database registration number NCT01835977. The Dutch Central Committee on Research Involving Human Subjects registration number NL50791.018.14.

PURPOSE Follow-up after colorectal cancer treatment with curative intent aims to detect recurrences and metachronous tumors in a timely manner. The objective of this study is to assess how recurrent disease presents and is diagnosed within scheduled follow-up according to the national guideline for the Netherlands. METHODS In a retrospective study of consecutive patients with colorectal cancer who were treated in 2 hospitals in the Netherlands, we identified patients with colon cancer who underwent surgery with curative intent between January 2007 and December 2012. Patients who developed recurrent disease were included for further analyses. RESULTS From a total of 446 patients who were been treated for colon carcinoma with curative intent, 74 developed recurrent disease (17%). In 43 of those patients (58%), recurrent disease was detected during a scheduled follow-up visit, with 41 (95%) being asymptomatic. Tumor marker testing, imaging, and colonoscopy identified all of these recurrences. In the remaining 31 patients with recurrent disease (42%), recurrence was found during non-scheduled interval visits; 26 (84%) of these patients were symptomatic. The most prevalent symptoms were abdominal pain, altered defecation, and weight loss. Patients with asymptomatic recurrences had a significantly higher overall survival compared with patients with symptomatic recurrences. CONCLUSIONS In this cohort, 42% of the recurrences after initial curative treatment for colon cancer were found during non-scheduled interval visits, mainly based on symptoms. Primary care physicians who take care of patients whose colon cancer might recur should be aware of the relatively high rate of symptomatic recurrences and of typical presenting symptoms.