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Purpose In order to avoid pedicle screw misplacement in posterior spinal deformity surgery, patient specific 3D‑printed guides can be used. An accuracy assessment of pedicle screw insertion can be obtained by superimposing CT-scan images from a preoperative plan over those of the postoperative result. The aim of this study is to report on the accuracy of drill guide assisted pedicle screw placement in thoracolumbar spinal deformity surgery by means of a superimpose CT-analysis. Methods Concomitant with the clinical introduction of a new technique for drill guide assisted pedicle screw placement, the accuracy of pedicle screw insertion was analyzed in the first patients treated with this technique by using superimpose CT-analysis. Deviation from the planned ideal intrapedicular screw trajectory was classified according to the Gertzbein scale. Results Superimpose CT-analysis of 99 pedicle screws in 5 patients was performed. The mean linear deviation was 0.92 mm, the mean angular deviation was 2.92° with respect to the preoperatively planned pedicle screw trajectories. According to the Gertzbein scale, 100% of screws were found to be positioned within the “safe zone”. Conclusion The evaluated patient specific 3D-printed guide technology was demonstrated to constitute a safe and accurate tool for precise pedicle screw insertion in spinal deformity surgeries. Superimpose CT-analysis showed a 100% accuracy of pedicle screw placement without any violation of the pedicle wall or other relevant structures. We recommend a superimpose CT-analysis for the first consecutive patients when introducing new technologies into daily clinical practice, such as intraoperative imaging, navigation or robotics.

Inspired by recent technological advances in the gaming industry, we used capture cards to create and LIVE-stream high quality 3D-images. With this novel technique, we developed a real-life stereoscopic 3D full-body illusion paradigm (3D projection). Unlike previous versions of the full-body illusion that rely upon unwieldy head-mounted displays, this paradigm enables the unobstructed investigation of such illusions with neuroscience methods (e.g., transcranial direct current stimulation, transcranial magnetic stimulation, electroencephalography, and near-infrared spectroscopy) and examination of their neural underpinnings. This paper has three aims: (i) to provide a step-by-step guide on how to implement 3D LIVE-streaming, (ii) to explain how this can be used to create a full-body illusion paradigm; and (iii) to present evidence that documents the effectiveness of our methods (de Boer et al., 2020), including suggestions for potential applications. Particularly significant is the fact that 3D LIVE-streaming is not GPU-intensive and can easily be applied to any device or screen that can display 3D images (e.g., TV, tablet, mobile phone). Therefore, these methods also have potential future clinical and commercial benefits. 3D LIVE-streaming could be used to enhance future clinical observations or educational tools, or potentially guide medical interventions with real-time high-quality 3D images. Alternatively, our methods can be used in future rehabilitation programs to aid recovery from nervous system injury (e.g., spinal cord injury, brain damage, limb loss) or in therapies aimed at alleviating psychosis symptoms. Finally, 3D LIVE-streaming could set a new standard for immersive online gaming as well as augmenting online and mobile experiences (e.g., video chat, social sharing/events).

Background: Spontaneous Haemoperitoneum in Pregnancy (SHiP) is a rare, but life-threatening complication of pregnancy that occurs predominantly in the third trimester of pregnancy and is associated with adverse pregnancy outcomes. Recently the largest case series in literature was published describing 11 Dutch cases of SHiP in women with endometriosis. Purpose: To investigate experiences, psychological impact, and quality of life after SHiP. Methods: A mixed-methods study was performed in women with a history of SHiP and their partners, including all known cases in the Netherlands between 2007 to 2015. Semi-structured in-depth interviews were organized between 2016 and 2017 and analysed thematically with a framework approach. Participants were asked to complete questionnaires investigating the impact of the event (Impact of Event Scale) and Quality of Life (RAND-36). Results: Out of a total of 11 known cases, 7 women agreed for be individually interviewed. From these, all women described a freeze response at the moment of SHiP, combined with either an anxious reaction or a survival mode mind-set. All women received psychological help after SHiP. Still, the feeling of not being heard by the medical staff was present in all women. Other themes such as postpartum period, bonding with their child, effect on daily life, reviving the event, and future pregnancies were also identified in the interviews. In regard to their partners, 3 were interviewed, hence no saturation was achieved. Finally, the questionnaires showed lower Quality of Life and an impact score of ≥ 8/10. Conclusion: SHiP had a profound impact on women and their partners. Dedicated psychological help should be offered to all women after experiencing SHiP.

To evaluate the effect of cervical pessary, as a strategy to prevent preterm birth (PTB), on the outcome of subsequent pregnancy and maternal quality of life 4 years after the index twin pregnancy.Between 2009 and 2012, the ProTWIN trial randomized women with a multiple pregnancy to pessary use vs standard care for the prevention of PTB. The trial showed no benefit in unselected women with a twin pregnancy, but showed a 60% reduction in poor perinatal outcomes in favor of the pessary group in the subgroup of women with a mid-trimester short cervix (cervical length 38 mm). All women were invited to participate in a follow-up study 4 years after their participation in the ProTWIN trial. In this follow-up study, maternal quality of life was assessed using the EQ-5D-3L questionnaire and women were asked separate questions about subsequent pregnancies. Results were compared between women who were randomized to the pessary vs the control group in the ProTWIN trial by calculating relative risk (RR) and 95% CI. Subgroup analysis was performed for women with a mid-trimester short cervix (cervical length 38 mm).Of the 813 women included in the ProTWIN trial, 408 (50.2%) participated in this follow-up study, comprising 228 randomized to the pessary group and 180 to the control group in the original trial. The median interval between participation in the ProTWIN trial and participation in this follow-up study was 4.1 (interquartile range (IQR), 3.9-7.1) years. Ninety-eight (24.0%) participants tried to conceive after their participation in the ProTWIN trial. Of those, 22 (22.4%) women did not have a subsequent pregnancy (no difference between pessary and control groups), seven (7.1%) women had at least one miscarriage but no live birth, and 67 (68.4%) women had at least one live birth (35 in the pessary vs 32 in the control group; RR, 0.93 (95% CI, 0.8-1.07)). In two women, the pregnancy outcome was unknown. Preterm delivery ( 37 weeks of gestation) of the first live birth occurred in three women in the pessary vs one woman in the control group (all singleton; RR, 2.57 (95% CI, 0.28-23.44)). No differences were found between the pessary and control groups in the subgroup of women with mid-trimester short cervix, but the numbers analyzed were small. The median health state index score was 0.95 (IQR, 0.82-0.95), with no difference between the pessary and control groups.Our findings suggest that there are no long-term effects of pessary use on the outcome of subsequent pregnancies and maternal quality of life. Data on obstetric outcome were limited due to the small numbers. © 2021 The Authors. Ultrasound in ObstetricsGynecology published by John WileySons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Background Pulmonary artery (PA) dilatation is often seen in pulmonary hypertension (PH) and is considered a long-term consequence of elevated pressure. The PA dilates over time and therefore may reflect disease severity and duration. Survival is related to the stage of the disease at the time of diagnosis and therefore PA diameter might be used to predict prognosis. This study evaluates the outcome of patients with pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH) and investigates whether PA diameter at the time of diagnosis is associated with mortality. Methods Patients visiting an outpatient clinic of a tertiary centre between 2004 and 2018 with a cardiac catheterisation confirmed diagnosis of PAH or CTEPH and a CT scan available for PA diameter measurement were included. PA diameter and established predictors of survival were collected (New York Heart Association (NYHA) class, N‑terminal pro-brain natriuretic peptide (NT-proBNP) level and 6‑min walking distance (6MWD)). Results In total 217 patients were included (69% female, 71% NYHA class ≥III). During a median follow-up of 50 (22–92) months, 54% of the patients died. Overall survival was 87% at 1 year, 70% at 3 years and 58% at 5 years. The mean PA diameter was 34.2 ± 6.2 mm and was not significantly different among all the diagnosis groups. We found a weak correlation between PA diameter and mean PA pressure ( r = 0.23, p Conclusion The prognosis of PAH and CTEPH is still poor. Known predictors of survival were confirmed, but PA diameter at diagnosis was not associated with survival in PAH or CTEPH patients.

Background Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC. Methods Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed. Results The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5–19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion. Conclusion The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

Objective: To determine the risk of overall preterm birth (PTB) and spontaneous PTB in a pregnancy after a caesarean section (CS) at term. Design: Longitudinal linked national cohort study. Setting: The Dutch Perinatal Registry (1999–2009). Population: 268 495 women with two subsequent singleton pregnancies were identified. Methods: A cohort study based on linked registered data from two subsequent pregnancies in the Netherlands. Main outcome measures: The incidence of overall PTB and spontaneous PTB with subgroup analysis on gestational age at first delivery and type of CS (planned or unplanned). Results: Of 268 495 women with a singleton first pregnancy who delivered at term, 15.76% (n = 42 328) had a CS. The incidence of PTB in the second pregnancy was 2.79% (n = 1182) in women with a previous CS versus 2.46% (n = 5570) in women with a previous vaginal delivery (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.07–1.21). This increased risk is mainly driven by an increased risk of spontaneous PTB after previous CS at term (aOR 1.50, 95% CI 1.38–1.70). Analysis for type of CS compared with vaginal delivery showed an aOR on spontaneous PTB of 1.86 (95% CI 1.58–2.18) for planned CS and an aOR of 1.40 (95% CI 1.24–1.58) for unplanned CS. Conclusions: CS at term is associated with a marginally increased risk of spontaneous PTB in a subsequent pregnancy. Tweetable abstract: Caesarean section at term is associated with a marginally increased risk of spontaneous PTB in a subsequent pregnancy.

Background The COVID-19 pandemic led to regional or nationwide lockdowns as part of risk mitigation measurements in many countries worldwide. Recent studies suggest an unexpected and unprecedented decrease in preterm births during the initial COVID-19 lockdowns in the first half of 2020. The objective of the current study was to assess the effects of the two months of the initial national COVID-19 lockdown period on the incidence of very and extremely preterm birth in the Netherlands, stratified by either spontaneous or iatrogenic onset of delivery, in both singleton and multiple pregnancies. Methods Retrospective cohort study using data from all 10 perinatal centers in the Netherlands on very and extremely preterm births during the initial COVID-19 lockdown from March 15 to May 15, 2020. Incidences of very and extremely preterm birth were calculated using an estimate of the total number of births in the Netherlands in this period. As reference, we used data from the corresponding calendar period in 2015–2018 from the national perinatal registry (Perined). We differentiated between spontaneous versus iatrogenic onset of delivery and between singleton versus multiple pregnancies. Results The incidence of total preterm birth Conclusion This study shows a decrease in iatrogenic preterm births during the initial COVID-19-related lockdown in the Netherlands in singletons. Future studies should focus on the mechanism of action of lockdown measures and reduction of preterm birth and the effects of perinatal outcome.

Objective To assess the association between preterm birth and cervical length after arrested preterm labor in high‐risk pregnant women. Methods In this post‐hoc analysis of a randomized clinical trial, transvaginal cervical length was measured in women whose contractions had ceased 48 h after admission for threatened preterm labor. At admission, women were defined as having a high risk of preterm birth based on a cervical length of

Simple Summary Favorable survival outcomes for patients with advanced-stage ovarian cancer are associated with complete cytoreduction. Enlarged cardiophrenic lymph node (CPLN) is commonly observed in advanced-stage epithelial ovarian cancer (AEOC); however, the prognostic impact of CPLN adenopathy is inconclusive. In this study, we evaluate the clinical outcomes of CPLN adenopathy in AEOC patients who underwent cytoreductive surgery. This systematic review and meta-analysis demonstrated that enlarged CPLN in preoperative imaging is highly associated with metastatic involvement. Patients with CPLN adenopathy had a significantly increased risk of recurrence of disease and dying from the disease in comparison to those without adenopathy, a finding likely related to more advanced disease in this group. Currently, there are no data that definitively demonstrate a therapeutic benefit of CPLN resection. Further randomized controlled trials should be conducted to definitively demonstrate whether CPLN resection at the time of cytoreductive surgery is beneficial. Abstract Purpose: To evaluate the clinical outcomes of enlarged cardiophrenic lymph node (CPLN) in advanced-stage epithelial ovarian cancer (AEOC) patients who underwent cytoreductive surgery. Methods: The Embase, Medline, Web of Science, Cochrane Library, and Google Scholar databases were searched for articles from the database inception to June 2021. Meta-analysis was conducted to determine the prognostic impact of surgical outcome, postoperative complication, and survival using random-effects models. Results: A total of 15 studies involving 727 patients with CPLN adenopathy and 981 patients without CPLN adenopathy were included. The mean size of preoperative CPLN was 9.1± 3.75 mm. Overall, 82 percent of the resected CPLN were histologically confirmed pathologic nodes. Surgical outcomes and perioperative complications did not differ between both groups. The median OS time was 42.7 months (95% CI 10.8–74.6) vs. 47.3 months (95% CI 23.2–71.2), in patients with and without CPLN adenopathy, respectively. At 5 years, patients with CPLN adenopathy had a significantly increased risk of disease recurrence (HR 2.14, 95% CI 1.82–2.52, p < 0.001) and dying from the disease (HR 1.74, 95% CI 1.06–2.86, p = 0.029), compared with those without CPLN adenopathy. CPLN adenopathy was significantly associated with ascites (OR 3.30, 95% CI 1.90–5.72, p < 0.001), pleural metastasis (OR 2.58, 95% CI 1.37–4.82, p = 0.003), abdominal adenopathy (OR 2.30, 95% CI 1.53–3.46, p < 0.001) and extra-abdominal metastasis (OR 2.30, 95% CI 1.61–6.67, p = 0.001). Conclusions: Enlarged CPLN in preoperative imaging is highly associated with metastatic involvement. Patients with CPLN adenopathy had a lower survival rate, compared with patients without CPLN adenopathy. Further randomized controlled trials should be conducted to definitively demonstrate whether CPLN resection at the time of cytoreductive surgery is beneficial.

IntroductionPreterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development.Methods and analysisThis is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16–20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11–14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers.Main outcomes are child cognition and behaviourAdditional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used.Ethics and disseminationAmsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results.Trial registration numberNL8933.

Objective Cardiotocography (CTG) is an important tool for fetal surveillance in severe early-onset fetal growth restriction (FGR). Assessment of the CTG is usually performed visually (vCTG). However, it is suggested that computerized analysis of the CTG (cCTG) including short term variability (STV) could more accurately detect fetal compromise. The objective of this study was to systematically review the literature on the association between cCTG and perinatal outcome and the comparison of cCTG with vCTG. Study design A systematic search was performed in MEDLINE, EMBASE and Google Scholar. Studies were included that assessed prognostic accuracy of STV or compared STV to vCTG in patients with FGR. Risk of bias and concerns about applicability were assessed with the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) instrument. Results Of the 885 records identified in the search, five cohort studies (387 patients) were included. We found no randomized studies comparing STV with visual CTG in patients with FGR. The risk of bias of all studies was generally judged as ‘low’. One small study found an association of low STV with neonatal acidosis. One study observed no association of STV with long-term outcome. Composite analysis of all five studies showed a non-significant relative risk for acidosis after a low STV of 1.4 (95% CI 0.6–3.2, N = 387). Further meta-analysis was hampered due to heterogeneity in outcome reporting and use of different thresholds. Conclusion The evidence from the included studies did not support an association of STV and short or long term outcome. However, available data are limited and heterogeneous, and influenced by management based on STV. Solid evidence from a randomized controlled trial comparing STV with vCTG including long term infant outcome is needed before STV can be used clinically for timing of delivery in patients with FGR.

Objective To assess the cost-effectiveness of treatment with nifedipine compared with atosiban in women with threatened preterm birth. Design An economic analysis alongside a randomised clinical trial (the APOSTEL III study). Setting Obstetric departments of 12 tertiary hospitals and seven secondary hospitals in the Netherlands and Belgium. Population Women with threatened preterm birth between 25 and 34 weeks of gestation, randomised for tocolysis with either nifedipine or atosiban. Methods We performed an economic analysis from a societal perspective. We estimated costs from randomisation until discharge. Analyses for singleton and multiple pregnancies were performed separately. The robustness of our findings was evaluated in sensitivity analyses. Main outcome measures Mean costs and differences were calculated per woman treated with nifedipine or atosiban. Health outcomes were expressed as the prevalence of a composite of adverse perinatal outcomes. Results Mean costs per patients were significantly lower in the nifedipine group [singleton pregnancies: euro34,897 versus euro43,376, mean difference (MD) -euro8479 [95% confidence interval (CI) -euro14,327 to -euro2016)]; multiple pregnancies: euro90,248 versus euro102,292, MD -euro12,044 (95% CI -euro21,607 to euro -1671). There was a non-significantly higher death rate in the nifedipine group. The difference in costs was mainly driven by a lower neonatal intensive care unit admission (NICU) rate in the nifedipine group. Conclusion Treatment with nifedipine in women with threatened preterm birth results in lower costs when compared with treatment with atosiban. However, the safety of nifedipine warrants further investigation. Tweetable abstract In women with threatened preterm birth, tocolysis using nifedipine results in lower costs when compared with atosiban.

Background Azathioprine and mercaptopurine exposure during conception and pregnancy has been considered safe in patients with inflammatory bowel disease (IBD). Its use is not associated with a higher risk of preterm birth or low birthweight. Data on the safety of tioguanine, an alternative thiopurine-derivate, in pregnant IBD patients is limited. In a small case series, tioguanine appeared safe for both mother and fetus. In this study, we describe the teratogenicity and safety of tioguanine during pregnancy in a large group of IBD patients. Methods We performed a preliminary analysis of our ongoing multicenter descriptive case series of female IBD patients who were treated with tioguanine at some point during their pregnancy. Data regarding disease and medication history, pregnancy course and neonatal outcomes, such as preterm birth, miscarriage, birthweight, Apgar scores and congenital abnormalities were collected by the treating physician. Results Seventy-three pregnancies, including three twin pregnancies were collected. Most women (80%) had Crohn’s disease and the mean age during delivery was 31 years (range 21-42). Tioguanine was used throughout the entire pregnancy in 89% with a median daily dose of 20 mg. Five (6.8%) of these pregnancies resulted in a miscarriage, all within the first 13 weeks. No congenital abnormalities were reported in all seventy-one live born children. In the singleton pregnancies the median birthweight was 3375 gram (IQR 3075-3739, N=61, 4 missing values) with a median gestational age of 39.0 weeks (IQR 38.3-40.0, N=61). Four children (6.5%) were born prematurely ( The median Apgar score after 1 and 5 minutes was respectively 9 (IQR 8-9, N=58) and 10 (IQR 9-10, N=59). Two neonates (3.4%), one born pre-and dysmature and the other a premature second-born twin, had an Apgar score ( Conclusion In this large case-series, tioguanine exposure during pregnancy was not associated with an increased risk of congenital abnormalities, low birthweight or preterm birth in IBD patients. These data support the safe use of tioguanine during pregnancy in IBD.

Aim of this study was to compare cardiovascular risk in women with and without inheritable thrombophilia after hypertensive disorders of pregnancy (HDP). Blood pressure, anthropometrics and blood samples were measured 9-13 years after early-onset ( 25 kg/m2 (43.8% vs. 53.1%, OR 0.69 95% CI (0.24–2.00)) or metabolic syndrome (18.8% vs. 13.3%, OR 1.51 95% CI (0.38–6.02)) were found. These data show similar cardiovascular risk profile in women with and without inheritable thrombophilia.

Background Evidence for an association between hospital volume and outcomes for liver surgery is abundant. The current Dutch guideline requires a minimum volume of 20 annual procedures per centre. The aim of this study was to investigate the association between hospital volume and postoperative outcomes using data from the nationwide Dutch Hepato Biliary Audit. Methods This was a nationwide study in the Netherlands. All liver resections reported in the Dutch Hepato Biliary Audit between 2014 and 2017 were included. Annual centre volume was calculated and classified in categories of 20 procedures per year. Main outcomes were major morbidity (Clavien–Dindo grade IIIA or higher) and 30‐day or in‐hospital mortality. Results A total of 5590 liver resections were done across 34 centres with a median annual centre volume of 35 (i.q.r. 20–69) procedures. Overall major morbidity and mortality rates were 11·2 and 2·0 per cent respectively. The mortality rate was 1·9 per cent after resection for colorectal liver metastases (CRLMs), 1·2 per cent for non‐CRLMs, 0·4 per cent for benign tumours, 4·9 per cent for hepatocellular carcinoma and 10·3 per cent for biliary tumours. Higher‐volume centres performed more major liver resections, and more resections for hepatocellular carcinoma and biliary cancer. There was no association between hospital volume and either major morbidity or mortality in multivariable analysis, after adjustment for known risk factors for adverse events. Conclusion Hospital volume and postoperative outcomes were not associated., This study analysed the association between hospital volume and postoperative outcomes in the nationwide Dutch Hepato Biliary Audit. A total of 5590 resections was performed across 34 centres with a median annual centre volume of 35 (i.q.r. 20–69) procedures. No association was found between hospital and postoperative outcomes. Cut‐off about right

The aim of the present work was to unravel which environmental drivers govern the dynamics of toxic dinoflagellate abundance as well as their associated paralytic shellfish toxins (PSTs), diarrhetic shellfish toxins (DSTs) and pectenotoxin-2 (PTX2) in Ambon Bay, Eastern Indonesia. Weather, biological and physicochemical parameters were investigated weekly over a 7-month period. Both PSTs and PTX2 were detected at low levels, yet they persisted throughout the research. Meanwhile, DSTs were absent. A strong correlation was found between total particulate PST and Gymnodinium catenatum cell abundance, implying that this species was the main producer of this toxin. PTX2 was positively correlated with Dinophysis miles cell abundance. Vertical mixing, tidal elevation and irradiance attenuation were the main environmental factors that regulated both toxins and cell abundances, while nutrients showed only weak correlations. The present study indicates that dinoflagellate toxins form a potential environmental, economic and health risk in this Eastern Indonesian bay.

Adenoid cystic carcinoma (ACC) of the Bartholin gland is a rare gynaecological entity. Despite its slow growth and inconspicuous presentation, vulvar ACC has a propensity for perineural invasion and is therefore associated with high local recurrence rates. We report a case of vulvar ACC in a 61-year-old woman with a prolonged swelling of the Bartholin gland. This patient presented with pulmonary metastases at the moment of histological diagnosis. The vulvar and the pulmonary lesions showed identical histology. Despite a history of human papilloma virus (HPV)-related usual type vulvar intra-epithelial neoplasia and cervical squamous cell carcinoma, the vulvar ACC was negative for both p16 immunohistochemistry and HPV-DNA. We conclude that HPV is not involved in the pathogenesis of pure ACC of the Bartholin gland. Additionally, we advocate a low threshold for performing biopsies of vulvar swellings in women aged >40 years, to rule out malignancy and to prevent diagnostic delays.

Background Mortality rates are high among hospitalized patients with COVID-19, especially in those intubated on the ICU. Insight in pathways associated with unfavourable outcome may lead to new treatment strategies. Methods We performed a prospective cohort study of patients with COVID-19 admitted to general ward or ICU who underwent serial blood sampling. To provide insight in the pathways involved in disease progression, associations were estimated between outcome risk and serial measurements of 64 biomarkers in potential important pathways of COVID-19 infection (inflammation, tissue damage, complement system, coagulation and fibrinolysis) using joint models combining Cox regression and linear mixed-effects models. For patients admitted to the general ward, the primary outcome was admission to the ICU or mortality (unfavourable outcome). For patients admitted to the ICU, the primary outcome was 12-week mortality. Findings A total of 219 patients were included: 136 (62%) on the ward and 119 patients (54%) on the ICU; 36 patients (26%) were included in both cohorts because they were transferred from general ward to ICU. On the general ward, 54 of 136 patients (40%) had an unfavourable outcome and 31 (23%) patients died. On the ICU, 54 out of 119 patients (45%) died. Unfavourable outcome on the general ward was associated with changes in concentrations of IL-6, IL-8, IL-10, soluble Receptor for Advanced Glycation End Products (sRAGE), vascular cell adhesion molecule 1 (VCAM-1) and Pentraxin-3. Death on the ICU was associated with changes in IL-6, IL-8, IL-10, sRAGE, VCAM-1, Pentraxin-3, urokinase-type plasminogen activator receptor, IL-1-receptor antagonist, CD14, procalcitonin, tumor necrosis factor alfa, tissue factor, complement component 5a, Growth arrest–specific 6, angiopoietin 2, and lactoferrin. Pathway analysis showed that unfavourable outcome on the ward was mainly driven by chemotaxis and interleukin production, whereas death on ICU was associated with a variety of pathways including chemotaxis, cell-cell adhesion, innate host response mechanisms, including the complement system, viral life cycle regulation, angiogenesis, wound healing and response to corticosteroids. Interpretation Clinical deterioration in patients with severe COVID-19 involves multiple pathways, including chemotaxis and interleukin production, but also endothelial dysfunction, the complement system, and immunothrombosis. Prognostic markers showed considerable overlap between general ward and ICU patients, but we identified distinct differences between groups that should be considered in the development and timing of interventional therapies in COVID-19. Funding Amsterdam UMC, Amsterdam UMC Corona Fund, and Dr. C.J. Vaillant Fonds.

OBJECTIVE: To report pregnancy outcomes of SHiP (spontaneous haemoperitoneum in pregnancy) and the association with endometriosis.DESIGN: Retrospective case note review.SETTING: Dutch referral hospitals for endometriosis.SAMPLE: Eleven women presenting with 15 events of SHiP.METHODS: In collaboration with the Dutch Working Group on Endometriosis, unpublished cases of SHiP that occurred in the Netherlands between 2010 and 2015 were retrieved.MAIN OUTCOME MEASURES: Maternal and perinatal mortality and morbidity.RESULTS: SHiP occurred predominantly in the second and third trimester of pregnancy. The earliest and major presenting symptom was an acute onset of abdominal pain, often combined with low haemoglobin levels or signs of fetal distress. Imaging was a diagnostic tool when free peritoneal fluid could be observed. For surgical treatment of the bleeding site, a midline laparotomy was mostly needed, the median estimated amount of blood loss was 2000 mL. No fetomaternal or perinatal mortality was reported, despite a high rate of preterm births (54.5%). In all women, endometriosis was diagnosed at a certain moment in time and therefore was probably involved in the pathogenesis of SHiP. Four women showed recurrence of SHiP. In one of these cases the second event of SHiP occurred in a subsequent pregnancy.CONCLUSION: Pregnancy outcomes of SHiP are improving when compared with previous reports, with absent fetomaternal and perinatal mortality in this recent series. Growing knowledge and adequate multidisciplinary intervention may have contributed to these favourable results. Increasing awareness of this serious complication of pregnancy is advocated, especially in women diagnosed with endometriosis.TWEETABLE ABSTRACT: Growing awareness of SHiP is advocated, especially in women diagnosed with endometriosis.

BACKGROUND Red blood cell (RBC) transfusion is associated with organ failure. The mechanism remains unknown, but may include adherence of blood cells to the microvasculature. We hypothesized that RBC-derived extracellular vesicles (EVs) interact with monocytes to activate endothelial cells. STUDY DESIGN AND METHODS Human umbilical vein endothelial cells were incubated with supernatant from fresh and stored RBC units either containing EVs or depleted from EVs, with or without the addition of immune cells. We measured expression of adhesion markers by flow cytometry and markers of coagulation and inflammation in the culture medium. We studied phagocytosis of EVs by monocytes by using confocal microscopy and flow cytometry. RESULTS Incubation of endothelial cells with monocytes alone did not induce up regulation of adhesion markers. The addition of both monocytes and supernatant from RBCs containing EVs resulted in up regulation of endothelial expression of intercellular adhesion molecule 1 and E-selectin when compared to baseline. Up regulation was absent when stimulated with RBC supernatant depleted from EVs. EVs are phagocytosed by monocytes, which was partly abrogated after coincubation with two different complement receptor 3 (CR3)-blocking antibodies. Addition of RBC-derived EVs also increased levels of von Willebrand factor (VWF). There were no differences between groups related to storage time. CONCLUSION EVs from RBC transfusion bags activate monocytes with subsequent up regulation of endothelial cell adhesion markers. EVs are phagocytosed by monocytes through CR3. Furthermore, these EVs proved to be a source of VWF. These effects are unrelated to storage time. Thereby, EVs from RBC transfusion bags induce a proinflammatory and procoagulant endothelial cell response.

About 80 % of all women affected by ovarian cancer present with advanced stage disease at the time of diagnosis. Achieving complete cytoreduction is complicated when many small tumor spots are found. Yet, complete cytoreduction is the most important determinant of survival. Application of a thermal plasma energy device to standard surgical instruments may help achieve complete cytoreduction. The ‘PlasmaJet® Device’ (Plasma Surgical, Inc., Roswell, GA, USA) is an electrically neutral device which emits a high–energy jet of argon plasma for direct tissue effects. We performed a literature review to investigate whether the use of the ‘PlasmaJet® Device’ in surgery of advanced stage ovarian carcinoma (FIGO IIIB-IV) is effective and safe. The primary outcome was the proportion of complete cytoreductions. The secondary outcomes were: complication rate, proportion of colostomies applied, histological findings, disease-free survival and overall survival. Five case series or reports were found, including a total of 77 patients with FIGO stage IIIC-IV ovarian cancer in whom the PlasmaJet® device was used for primary or interval debulking. Complete cytoreduction was obtained in 79% of the patients. Apart from one pneumothorax after extensive surgery, but no harm or additional complications related to the use of the PlasmaJet® Device were reported. Data on disease-free survival or overall survival were not reported. These findings suggest that the PlasmaJet® Device is an efficient and safe innovative surgical device for debulking surgery with encouraging results. We have proposed an RCT in which we will compare feasibility, safety and effectiveness aspects of the use of the PlasmaJet® versus conventional electrosurgery in advanced stage epithelial ovarian cancer (FIGO IIIB-IV).

BackgroundAs a result of improvements in the early resuscitation phase of trauma, mortality is largely driven by later mortality due to multiple organ dysfunction syndrome (MODS), which may be mediated by an early overdrive in the host immune response. If patients at risk for MODS could be identified early, preventive treatment measures could be taken. The aim of this study is to investigate whether specific biomarkers are associated with MODS.MethodsMultiple trauma patients presenting to the Amsterdam University Medical Centers, location Academic Medical Center, between 2012 and 2018 with an Injury Severity Score of 16 or higher were sampled on arrival at the emergency department. A wide variety of inflammatory cytokines, endothelial and lung-specific markers were determined. Comparisons were made between patients with and without MODS. Univariate and multivariate logistic regression was used to determine associations between specific biomarkers and MODS. A p value of 0.05 was considered to be statistically significant.ResultsIn total, 147 multiple trauma patients were included. Of these, 32 patients developed MODS (21.7%). Patients who developed MODS were more severely injured, had more traumatic brain injury and showed more deranged markers of coagulation when compared with patients without MODS. Overall, both proinflammatory and anti-inflammatory cytokines were higher in patients with MODS, indicative of a host immune reaction. In the multivariate analysis, the combination of anti-inflammatory proteins interleukin 1 receptor antagonist (IL-1RA) (OR 1.27 (1.07–1.51), p=0.002) and Clara cell protein 16 (CC-16) (1.06 (1.01–1.05), p=0.031) was most strongly associated with the development MODS.ConclusionsIn trauma, anti-inflammatory proteins IL-1RA and CC-16 have the potential to early identify patients at risk for development of MODS. Further research is warranted to prospectively validate these results.Level of evidencePrognostic study, level III.

Recent theories suggest that self-consciousness, in its most elementary form, is functionally disconnected from the phenomenal body. Patients with psychosis frequently misattribute their thoughts and actions to external sources; and in certain out-of-body experiences, lucid states, and dreams body-ownership is absent but self-identification is preserved. To explain these unusual experiences, we hypothesized that self-identification depends on inferring self-location at the right angular gyrus (i.e., perspective-taking). This process relates to the discrimination of self-produced signals (endogenous attention) from environmental stimulation (exogenous attention). Therefore, when this mechanism fails, this causes altered sensations and perceptions. We combined a Full-body Illusion paradigm with brain stimulation (HD-tDCS) and found a clear causal association between right angular gyrus activation and alterations in self-location (perspective-taking). Anodal versus sham HD-tDCS resulted in: a more profound out-of-body shift (with reduced sense of agency); and a weakened ability to discriminate self from other perspectives. We conclude that self-identification is mediated in the brain by inferring self-location (i.e., perspective-taking). Self-identification can be decoupled from the bodily self, explaining phenomena associated with disembodiment. These findings present novel insights into the relationship between mind and body, and may offer important future directions for treating psychosis symptoms and rehabilitation programs to aid in the recovery from a nervous system injury. The brain's ability to locate itself might be the key mechanism for self-identification and distinguishing self from other signals (i.e., perspective-taking).

Background Twelve percent of the Dutch population consists of non-Western immigrant women with an incidence of breast cancer that has risen from 2,9% in 2005 to 5% in 2015. For the second generation of these women the incidence of breast cancer is expected to meet the native Dutch population rates soon, partly due to adoption of Western style dietary habits and physical activity. Chemotherapeutic treatment (CT) for breast cancer is associated with increased body fatness and interventions to prevent this increase are currently explored. Whether perceptions on cancer and treatment differ between non-Western immigrant women than for Dutch women needs to be evaluated before these interventions can be set up. This study aimed to explore cultural and religious differences on women's perceptions of the diagnosis of breast cancer and changes in physical activity and eating habits during chemotherapy treatment. Methods A longitudinal qualitative multiple case study was conducted. Newly diagnosed women with breast cancer were recruited and purposively selected (n=23, non-immigrant) from six hospitals in the Netherlands. Semi structured interviews were conducted three times (in total 69): before start of CT, halfway and after CT. In addition 38 women (20 non-immigrant and 18 immigrant) were recruited and interviewed after finishing CT. All interviews (n=107, from 61 women) were audiotaped and transcribed verbatim. A thematic content analysis approach was used. Results All 43 non-immigrant women, mean age 51,1 yrs. and 18 immigrant women mean age 43,2 yrs., experienced known side effects from CT. Loss of hair and sometimes the breast appeared to be especially for immigrant women a shocking experience and for some even a loss of femininity. Most of the women perceived to have received incomplete and often unclear information from hospitals about weight and CT treatment. Immigrant women participating the Ramadan during treatment encountered resistance from their physicians. Weight gain during period of CT was higher among immigrant women (mean 13,1 kg, 4-28 kg) than among non-immigrant women (mean 2,5 kg, 2-9 kg). Although both groups said to be less physically active and complained about fatigue, non-immigrant women trying to maintain daily structure and were more active with their diet than most immigrants. Immigrant women expressed cancer as a taboo in their culture impeding them to talk openly about their illness, only when side effects of CT such as hair loss were visible they found it inevitable. Cancer was associated with death at time of diagnosis. For most immigrants and a few non-immigrants this was considered a religious ordeal from Allah or God, these women perceived less influence on their behavior during treatment. Most non-religious women perceived breast cancer as bad luck, stress or heredity. Conclusion Especially immigrant women experienced little respect for their culture and insufficient information about treatment. Non-immigrants had a need to actively contribute to their treatment while this need was less obvious for immigrants. Probably because they felt not encouraged by their religion and culture. Citation Format: de Kruif AJ, Derks MJ, de Boer MR, Winkels R, Visser M, Kampman E, Westerman MJ. Cultural and religious differences during breast cancer treatment between Dutch and non-Western immigrant women. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-28.

Background: Transfusion of red blood cells (RBCs) is associated with adverse outcome, but the causative factor is unknown. Extracellular vesicles (EVs) have pro-inflammatory properties. We hypothesized that EVs released from both fresh and stored RBC products can induce a host inflammatory response in a dose-dependent manner. Methods: Whole blood was incubated with supernatant from RBC units stored for different time periods, either containing (different numbers of) EVs or depleted from EVs. Results: Incubation with both fresh and stored supernatant containing EVs induced a strong host response with production of TNF, IL-6 and IL-8. In supernatant depleted from EVs, this host response was completely abrogated. IL-10 levels were not affected. EV-induced host response was both dependent on the number of EVs as well as on storage time. Conclusions: EVs from both fresh and stored RBC units illicit a strong inflammatory host response in recipients and may therefore contribute to adverse outcome of RBC transfusion.

BACKGROUND: Biological phenotypes have been identified within several heterogeneous pulmonary diseases, with potential therapeutic consequences. OBJECTIVE: To assess whether distinct biological phenotypes exist within surgical patients, and whether development of postoperative pulmonary complications (PPCs) and subsequent dependence of intra-operative positive end-expiratory pressure (PEEP) differ between such phenotypes. SETTING: Operating rooms of six hospitals in Europe and USA. DESIGN: Secondary analysis of the 'PROtective Ventilation with HIgh or LOw PEEP' trial. PATIENTS: Adult patients scheduled for abdominal surgery who are at risk of PPCs. INTERVENTIONS: Measurement of pre-operative concentrations of seven plasma biomarkers associated with inflammation and lung injury. MAIN OUTCOME MEASURES: We applied unbiased cluster analysis to identify biological phenotypes. We then compared the proportion of patients developing PPCs within each phenotype, and associations between intra-operative PEEP levels and development of PPCs among phenotypes. RESULTS: In total, 242 patients were included. Unbiased cluster analysis clustered the patients within two biological phenotypes. Patients with phenotype 1 had lower plasma concentrations of TNF-α (3.8 [2.4 to 5.9] vs. 10.2 [8.0 to 12.1] pg ml; P

Objective Doppler ultrasonographic assessment of the cerebroplacental ratio (CPR) and middle cerebral artery (MCA) is widely used as an adjunct to umbilical artery (UA) Doppler to identify fetuses at risk of adverse perinatal outcome. However, reported estimates of its accuracy vary considerably. The aim of this study was to review systematically the prognostic accuracies of CPR and MCA Doppler in predicting adverse perinatal outcome, and to compare these with UA Doppler, in order to identify whether CPR and MCA Doppler evaluation are of added value to UA Doppler. Methods PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched, from inception to June 2016, for studies on the prognostic accuracy of UA Doppler compared with CPR and/or MCA Doppler in the prediction of adverse perinatal outcome in women with a singleton pregnancy of any risk profile. Risk of bias and concerns about applicability were assessed using the QUADAS‐2 (Quality Assessment of Diagnostic Accuracy Studies‐2) tool. Meta‐analysis was performed for multiple adverse perinatal outcomes. Using hierarchal summary receiver–operating characteristics meta‐regression models, the prognostic accuracy of CPR vs MCA Doppler was compared indirectly, and CPR and MCA Doppler vs UA Doppler compared directly. Results The search identified 4693 articles, of which 128 studies (involving 47 748 women) were included. Risk of bias or suboptimal reporting was detected in 120/128 studies (94%) and substantial heterogeneity was found, which limited subgroup analyses for fetal growth and gestational age. A large variation was observed in reported sensitivities and specificities, and in thresholds used. CPR outperformed UA Doppler in the prediction of composite adverse outcome (as defined in the included studies) (P, This article's abstract has been translated into Spanish and Chinese. Follow the links from the abstract to view the translations. This article has been selected for Journal Club. Click here to view slides and discussion points.

Objective: This study explored the long-term impact of a Total Laryngectomy (TL) on the partner and on the relationship between laryngectomees and their partners. Methods: 151 laryngectomees and 144 partners completed questionnaires assessing the psychosocial impact of a TL on the partner (quality of life, anxiety and depression, loss of control, fear, hopelessness, post-traumatic growth, caregiving burden) and on the spousal relationship (change in the quality of the spousal relationship and openness to discussion of the illness in the family). Results: A considerable number of partners of laryngectomees experience a psychosocial impact of the consequences of the TL, specifically on their social life (35%) and on their sexual relationship (31%). Also, the tendency of other people to neglect their laryngectomized life companion, affects more than half of the partners negatively. Clinical levels of anxiety and depression were found in around 20% of the partners. The consequences of a TL has a negative change on the sexual functioning for more than 30% of both laryngectomees and partners, the communication for around one fifth of both laryngectomees and partners, and feelings of dependency of the partner for one third of the laryngectomees. Conclusions: A TL has a considerable impact on the psychosocial life of partners of laryngectomees and on the spousal relationship. The findings of this explorative study sets the stage for structural screening on the need for support, not only for patients, but also for their partners. Sexuality and intimacy should be part of this screening. (C) 2015 Elsevier Ltd. All rights reserved.

Background Laparoscopic left lateral sectionectomy (LLLS) has been associated with shorter hospital stay and reduced overall morbidity compared with open left lateral sectionectomy (OLLS). Strong evidence has not, however, been provided. Methods In this multicentre double-blind RCT, patients (aged 18–80 years with a BMI of 18–35 kg/m2 and ASA fitness grade of III or below) requiring left lateral sectionectomy (LLS) were assigned randomly to OLLS or LLLS within an enhanced recovery after surgery (ERAS) programme. All randomized patients, ward physicians and nurses were blinded to the procedure undertaken. A parallel prospective registry (open non-randomized (ONR) versus laparoscopic non-randomized (LNR)) was used to monitor patients who were not enrolled for randomization because of doctor or patient preference. The primary endpoint was time to functional recovery. Secondary endpoints were length of hospital stay (LOS), readmission rate, overall morbidity, composite endpoint of liver surgery-specific morbidity, mortality, and reasons for delay in discharge after functional recovery. Results Between January 2010 and July 2014, patients were recruited at ten centres. Of these, 24 patients were randomized at eight centres, and 67 patients from eight centres were included in the prospective registry. Owing to slow accrual, the trial was stopped on the advice of an independent Data and Safety Monitoring Board in the Netherlands. No significant difference in median (i.q.r.) time to functional recovery was observed between laparoscopic and open surgery in the randomized or non-randomized groups: 3 (3–5) days for OLLSversus 3 (3–3) days for LLLS; and 3 (3–3) days for ONRversus 3 (3–4) days for LNR. There were no significant differences with regard to LOS, morbidity, reoperation, readmission and mortality rates. Conclusion This RCT comparing open and laparoscopic LLS in an ERAS setting was not able to reach a conclusion on time to functional recovery, because it was stopped prematurely owing to slow accrual. Registration number: NCT00874224 (https://www.clinicaltrials.gov).

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose ( P < 0.001). Grade 3 adverse events occurred in only 2 patients in the 600-mg arm, 4 patients in the 900-mg arm, and 5 patients in the 1,200-mg arm. No significant differences in the bacteriological response were observed. Higher daily doses of rifampin (900 and 1,200 mg) resulted in a more than proportional increase in rifampin exposure in plasma and were safe and well tolerated when combined with other first-line anti-TB drugs for 2 months, but they did not result in improved bacteriological responses in patients with pulmonary TB. These findings have warranted evaluation of even higher doses of rifampin in follow-up trials. (This study has been registered at ClinicalTrials.gov under identifier NCT00760149.)

To detect the presence of bovine herpesvirus (BoHV) type 4 in New Zealand dairy cows with clinical metritis.Serum samples taken from 92 dairy cows with clinical metritis, each from a different farm, were tested for the presence of antibodies against BoHV-4 using a commercially available, indirect ELISA. Peripheral blood mononuclear cells (PBMC) were collected from 10 BoHV-4 seropositive cows, and PBMC were examined by a pan-herpesvirus nested PCR to detect herpesvirus. PCR products were sequenced directly and a proportion of the PCR products were cloned and sequenced to identify the virus present.Antibodies to BoHV-4 were detected in 23/92 (25%) serum samples. The pan-herpesvirus PCR was positive in 8/10 PBMC samples. Cloning and sequencing identified that all of the eight PCR-positive PBMC contained bovine lymphotropic herpesvirus (BLHV); no BoHV-4 DNA was detected.This study reports the finding of the presence of apparent antibodies to BoHV-4, and BLHV DNA in New Zealand dairy cows affected by metritis.Bovine herpesvirus type 4 and BLHV are reported to have the potential to cause reproduction failure in cows. This is the first report of apparent BoHV-4 antibodies, and BLHV in New Zealand. The importance and epidemiology of these viruses in cattle in New Zealand requires further investigation.

Item does not contain fulltext Severe dengue is characterised by thrombocytopenia, plasma leakage and bleeding. Platelets are important for preservation of endothelial integrity. We hypothesised that platelet activation with secondary platelet dysfunction contribute to plasma leakage. In adult Indonesian patients with acute dengue, we measured platelet activation status and the response to the platelet agonist TRAP using flow cytometer-based assays. Patients were monitored daily for plasma leakage by ultrasonography. Acute dengue was associated with platelet activation with an increased expression of the activated fibrinogen receptor (alphaIIbbeta3), the lysosomal marker CD63 and the alpha-granule marker CD62P (P-selectin). Upon maximal platelet activation by TRAP, platelet function defects were observed with a significantly reduced maximal activated alphaIIbbeta3 and CD63 expression and reduced platelet-monocyte and platelet-neutrophil complexes. Patients in the lowest tertile of activated alphaIIbbeta3 and CD63 expression had an odds ratio for plasma leakage of 5.2 (95% confidence interval [CI] 1.3-22.7) and 3.9 (95% CI 1.1-13.7), respectively, compared to the highest tertile. Platelet-derived serotonin has previously been related to plasma leakage and we found increased intra-platelet serotonin concentrations in our patients. In conclusion, platelet activation with platelet function alterations can be found in patients with acute dengue and this may contribute to dengue-associated plasma leakage.

Objective To evaluate the performance of a directed non-invasive prenatal testing method of cell-free DNA analysis for fetal trisomy 21 (T21) by shipping the whole blood samples from Europe to a laboratory in the USA. Methods A European multicenter prospective, consecutive cohort study was performed enrolling pregnant women from Sweden and the Netherlands. Blood samples were drawn just prior to a planned of invasive diagnostic procedure in a population at increased risk for fetal T21 and then shipped to the USA without any blood processing. Chromosome-selective sequencing was carried out on chromosome 21 with reporting high risk or low risk of T21. Karyotyping or rapid aneuploidy detection was used as the clinical reference standard. Results Of the 520 eligible study subjects, a T21 test result was obtained in 504/520 (96.9%). Risk assessment was accurate in 503/504 subjects (99.8%). There was one false negative result for T21 (sensitivity 17/18, 94.4%, and specificity 100%). Conclusion This is the first prospective European multicenter study showing that non-invasive prenatal testing using directed sequencing of cell-free DNA applied to blood samples shipped across the Atlantic Ocean, is highly accurate for assessing risk of fetal T21. © 2013 John Wiley & Sons, Ltd.

Objective The mechanisms underlying obesity-related hypertension are incompletely understood. Microvascular dysfunction might play a role by increasing peripheral vascular resistance (PVR). Metabolic and microvascular effects of insulin are impaired in obesity, but how these impairments contribute to disturbed blood pressure homeostasis is unclear. Specifically, it is unknown whether local microvascular vasoactive effects of insulin play a role in determining systemic vascular resistance. The aim of this study was to investigate the association between PVR and local microvascular effects of insulin. Design and Methods Thirty-seven healthy, overweight subjects (age 25-55 years, BMI 25-30 kg/m2) were cross-sectionally studied. Local insulin-mediated vasodilation was measured using skin laser Doppler fluxmetry combined with transcutaneous iontophoresis of insulin. For comparison, local vasodilatory effects of acetylcholine and sodium nitroprusside were measured. PVR was calculated from mean arterial pressure and cardiac output, assessed by pulse-dye densitometry. Results PVR was inversely correlated with insulin-mediated vasodilation (r = −0.50; P < 0.01). This finding was maintained after adjustment for age, sex, blood pressure, and smoking. PVR was not associated with local microvascular effects of acetylcholine. Conclusions Our study in overweight subjects suggests that insulin's role in the microvasculature may contribute to blood pressure control.

Objective Transfusion-related acute lung injury is the leading cause of transfusion-related mortality. Preclinical studies have shown that aged RBCs can induce transfusion-related acute lung injury in the presence of a "first hit" (e.g., sepsis). Clinical studies, however, show conflicting results on this matter. We tested whether maximally stored RBCs are able to induce lung injury in the presence of a "first hit" in humans (Dutch Trial Register: NTR4455). Design Open-label, randomized controlled trial. Patients Healthy male volunteers. Interventions Eighteen healthy male volunteers donated one unit of autologous RBCs 2 or 35 days before the experiment. The experiment was started by infusion of 2 ng/kg lipopolysaccharide ("first hit"). After 2 hours, volunteers received normal saline (n = 6), 2-day stored transfusion (n = 6), or 35-day stored transfusion (n = 6) ("second hit"). Blood was sampled hourly. Six hours after transfusion, the diffusion capacity of the lungs for carbon monoxide was tested and volunteers underwent spirometry, chest x-ray study, and a bronchoalveolar lavage. Measurements and main results All volunteers fulfilled sepsis criteria after lipopolysaccharide injection. The stored blood transfusion did not result in significant changes in either hemodynamic or respiratory variables compared with the control groups. Furthermore, chest x-rays, lung function, and PaO2/FIO2 ratios did not differ between groups. Transfusion of stored autologous RBCs did not result in an increased level of protein in the lungs or neutrophil influx. Conclusions Transfusion of 35-day stored autologous RBCs in the presence of endotoxemia does not result in lung injury in humans.

Summary. Background: Theplateletcountvariesconsiderablybetween individuals, butwithin an individual the plateletcountis remarkably stable over time. Mechanisms controlling theplatelet count are not yet established. Objective: In the presentstudy, we tested the hypothesis that the liver is important incontrollingthecirculatingplateletcount,astheliveristhemainproducer of thrombopoietin. Methods: We compared theplatelet count prior to and after liver transplantation in> 250patientstransplantedforfamilialamyloidoticpolyneur-opathy (FAP). In contrast to most patients undergoing livertransplantation, patients with FAP have normal liver functionbefore transplantation. Furthermore, we compared plateletcounts in 89 living liver donors with the platelet count in therecipientsofthesegrafts.Finallywecomparedplateletcountsindonor-recipient pairs of hematopoietic stem cells. Results andconclusions: The platelet count prior to transplantation corre-lated with the platelet count at 3 or 12 months after transplan-tation in patients with FAP ( r = 0.48, P < 0.0001 at3 months, r = 0.39, P < 0.0001 at 12 months), whereas theplatelet count in a living liver donor did not correlate with theplatelet count in the recipient at 3 or 12 months aftertransplantation (r =0.16,P = 0.26 at 3 months, r = 0.11,P = 0.30at12 months).Theplateletcountofrelateddonorsofhematopoieticstemcellscorrelatedwiththeplateletcountintherecipient after transplantation ( r = 0.25, P = 0.011). Conclu-sions: These results suggest that the liver, in spite of being theprime producer of thrombopoietin, does not dictate thecirculating platelet count, whereas the bone marrow doesappear to play a role.Keywords: bone marrow transplantation, homeostasis, livertransplantation, platelet.IntroductionBlood platelets play a pivotal role in hemostasis and throm-bosis as evidenced by the bleeding tendency of patients withqualitative or quantitative platelet defects, and the efficacy ofanti-platelet drugs in the primary or secondary prevention ofarterial thrombosis. The average platelet count in humansvaries substantially between individuals, ranging from 150 000to 350 000 lL

a b s t r a c t Background: Studies have shown that self-sampling for hrHPV testing (HPV self-sampling) is highly acceptable to women, increases screening participation rate, and may therefore further reduce cervi- cal cancer incidence. However, it is important to clinically validate HPV self-sampling procedures for screening purposes. Objectives: Clinical validation of combined brush-based self-sampling with GP5+/6+-PCR EIA for primary cervical screening. In addition, HPV type-specific agreement between sample types and acceptability of brush-based self-sampling were evaluated. Study design: 135 women referred for colposcopy took a self-sample at home prior to vaginal- and cervical sampling by a gynaecologist. All women were biopsied for histology. HPV testing was done by GP5+/6+- PCR EIA, with genotyping by reverse line blotting (RLB). Acceptability of sampling methods was measured with a questionnaire. Results: In this outpatient population, hrHPV test results showed good concordance between self-samples and physician-taken cervical scrapes (86%, k = 0.70), with sensitivities and specificities for CIN2+ that did not differ significantly (93% and 51%, 91% and 51%, respectively (P = 1.0)). The clinical sensitivity of brush-based self-sampling combined with GP5+/6+-PCR EIA hrHPV testing for detection of CIN2+ was non-inferior to that of hrHPV testing on physician-taken cervical samples (P = 0.018). In addition, hrHPV genotyping results were highly concordant between sample types, with almost perfect agreement for HPV16 (k = 0.81) and HPV18 (k = 0.92). Finally, 91% of participants described brush-based self-sampling as easy-to-use. Conclusions: Brush-based self-sampling in combination with GP5+/6+-PCR EIA hrHPV testing is acceptable to women and valid for assessing the risk of CIN2+ in comparison to hrHPV testing on physician-taken scrapes. In addition, there was high concordance of HPV genotyping results. Therefore, this HPV self

Accurate measurement of material strength at small scales is of critical importance for the design and manufacture of reliable micro- and nanoscale devices. Many materials of interest, e.g., polycrystalline silicon (polysilicon) and silicon carbide, are brittle, with statistical strength distributions. Therefore, strength quantification requires a large number of tests accurately performed on a practical platform. Here, analysis and testing of a compact on-chip microtensile test system, recently presented in a brief communication [Hazra et al., Journal of Micromechanics & Microengineering, 2009], is expanded significantly. We present new data on strength, alignment precision, temperature distribution, compliance calibration, stiffness ratio, force calibration, and effect of monolayer film coverage. High force (up to 30 mN) is applied to a 70-μm-long freestanding tensile bar (nominally of 2 μm width and 2.25 μm height) by cooling a thermal actuator (TA) that has gripped a crosshead via a prehensile mechanism. According to finite element analysis, specimen heating is small (

A 35-year-old primigravida, pregnant after in-vitro fertilization, was seen because of a trisomy 13/trisomy 18 (T13/T18) risk of 1:55, based on the result of her first-trimester combined test. She elected for non-invasive prenatal testing (NIPT) at 14 + 5 weeks' gestation, which was positive for T13. After counseling, the patient elected to undergo amniocentesis. Quantitative fluorescence polymerase chain reaction (QF-PCR) showed no signs of trisomy, and full karyotyping confirmed a normal 46,XY result. Analysis of the published literature on NIPT for T13 gives an overall detection rate of 91.6%, with a false-positive rate of 0.097%. Based on this detection rate, hypothetical calculations show that the positive predictive value is highly dependent on the prevalence of the disease, resulting in an unfavorable balance between benefit and harm in a general population.