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To assess the economic impact of introducing the soluble FMS-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test into clinical practice in the United Kingdom (UK).Economic model estimating the incremental value of the information from a UK National Health Service (NHS) payer perspective generated by the sFlt-1/PlGF ratio test, compared with current diagnostic procedures, in guiding the management of women with suspected pre-eclampsia. The economic model estimated costs associated with the diagnosis and management of pre-eclampsia in women between 24 weeks and 36 weeks + 6 days of gestation managed in either a 'test' scenario in which the sFlt-1/PlGF test is used in addition to current diagnostic procedures, or a 'no-test' scenario in which clinical decisions are based on current diagnostic procedures alone. Test characteristics and resource use were derived from PROGNOSIS, a non-interventional study in women presenting with clinical suspicion of pre-eclampsia. The main outcome measure from the economic model was the cost per patient per episode of care (from first suspicion of pre-eclampsia to birth).Introduction of the sFlt-1/PlGF ratio test is expected to result in cost savings of £344 per patient compared with a 'no-test' scenario. Savings are generated primarily through an improvement in diagnostic accuracy and a reduction in unnecessary hospitalisation.The sFlt-1/PlGF ratio test has the potential to improve clinical decision-making, reducing unnecessary hospitalisation of women at low risk of developing pre-eclampsia, and ensuring that those women at higher risk are identified and managed appropriately.

To assess the association of a serum soluble fms-like tyrosine kinase 1-to-placental growth factor (sFlt-1-to-PlGF) ratio of greater than 38 with time to delivery and preterm birth.Secondary analysis of an observational cohort study that included women 18 years of age or older from 24 to 36 6/7 weeks of gestation at their first study visit with suspected (not confirmed) preeclampsia. Participants were recruited from December 2010 to January 2014 at 30 sites in 14 countries. A total of 1,041 women were included in time-to-delivery analysis and 848 in preterm birth analysis.Women with an sFlt-1-to-PlGF ratio greater than 38 (n=250) had a 2.9-fold greater likelihood of imminent delivery (ie, delivery on the day of the test) (Cox regression hazard ratio 2.9; P

The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear.We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks.In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3).An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).

Eine prazise Vorhersage der Praeklampsie (PE) kann dazu beitragen, mutterliche und kindliche Morbiditat und Mortalitat zu reduzieren. Der Quotient aus loslicher fms-like Tyrosinkinase 1 (sFlt-1) und plazentarem Wachstumsfaktor (PlGF) ist bei Frauen, die eine PE entwickeln, erhoht. In dieser Studie wurde der sFlt-1/PlGF-Quotient als Vorhersagemarker untersucht. In dieser doppelblinden, nicht-interventionellen Studie wurde der sFlt-1/PlGF-Quotient bei Frauen mit klinischem Verdacht auf PE (24 bis 36+6 Schwangerschaftswochen) bestimmt. Der primare Endpunkt der Studie war erstens zu zeigen, dass ein sFlt-1/PlGF-Quotient unterhalb des ermittelten Trennwerts das Auftreten von PE innerhalb von einer Woche ausschliest. Zweitens, dass ein sFlt-1/PlGF-Quotient oberhalb des Trennwerts das Auftreten von PE innerhalb von vier Wochen vorhersagt. Sekundare Endpunkte waren die Assoziation von sFlt-1/PlGF Quotient mit mutterlichen oder kindlichen Komplikationen. In einer Kohorte von 500 Patientinnen wurde ein sFlt-1/PlGF-Quotient Trennwert von 38 fur die Vorhersage der PE ermittelt. Dieser Trennwert wurde in einer Kohorte von 550 weiteren Patienten validiert. Fur die Gesamtkohorte konnte gezeigt werden, dass das Auftreten einer PE innerhalb einer Woche mit einem negativen Vorehrsagewert von 99,1% (95% Konfidenzintervall [CI], 98,2 bis 99,6), mit einer Sensitivitat von 85,7% (95% CI, 72,8 to 94,1) und einer Spezifitat von 79,1% (95% CI, 76,5 bis 81,6) ausgeschlossen werden kann. Das Auftreten einer PE innerhalb vier Wochen konnte mit einem positiven Vorhersagewert von 38,6% (95% CI, 32,6 bis 45,0), mit einer Sensitivitat von 70,3% (95% CI, 61,9 bis 77,8) und einer Spezifitat von 83,1% (95% CI, 80,5 bis 85,5) vorhergesagt werden. Hohe sFlt-1/PlGF Quotienten waren mit fetalen Komplikationen vergesellschaftet. Ein sFlt-1/PlGF Quotient < 38 kann das Auftreten einer PE innerhalb von einer Woche bei Patientinnen mit klinischem Verdacht auf Praeklampsie sicher ausschliesen.

Dysregulated angiogenic factors in the maternal circulation, including high soluble fms-like tyrosine kinase-1 (sFlt-1) and low placental growth factor (PlGF), as well as their ratio (sFlt1/PlGF), have been investigated as a diagnostic and prediction marker of preeclampsia. These circulating markers may represent markers for syncytiotrohoblast stress and placentally associated pregnancy complications, which represent major threats to maternal and offspring health globally. The talk will present recently published results from the PROGNOSIS [1] , [2] study as well as discuss future potential clinical and research implications of the study findings. PROGNOSIS was a prospective, multicenter, observational study in pregnancy where preeclampsia was suspected (gestational weeks 24 to 36 + 6 days). Maternal serum sFlt-1 and PlGF were measured after delivery (the results were unknown for clinicians) using Elecsys® sFlt-1 and PlGF assays (cobas e electrochemiluminescence immunoassay platform). The results from the development and validation cohorts (n = 500 and 550 pregnancies) identified an sFlt-1/PlGF ratio cut-off of 38 to optimally predict preeclampsia and that a ratio of ⩽38 is useful for predicting short-term absence of preeclampsia in women in whom the syndrome is suspected clinically [1] . In our second PROGNOSIS published paper [2] , we found that pregnancies with an sFlt-1/PlGF ratio >38 had three-times greater likelihood of preterm delivery and a substantially shorter remaining time to delivery than women with an sFlt-1/PlGF ratio of 38 or lower, whether or not they developed preeclampsia. Women who had iatrogenic preterm delivery (without preeclampsia) had higher median sFlt-1/PlGF ratios at the first study visit versus women with spontaneous preterm or at-term delivery. Clinical implications include the need for testing whether the use of the sFlt1/PlGF ratio to guide clinical decisions, as compared with usual care, will improve clinical outcome for mother and offspring. If cost-efficient, the use of circulating biomarkers can revolutionize the obstetric surveillance in countries that can offer such follow-up.

Introduction Clinical signs and symptoms of preeclampsia are known to be poorly predictive of who will develop the condition, prompting the investigation of angiogenic biomarkers as potential diagnostic and predictive aids. The Elecsys® immunoassay soluble fms-like tyrosine kinase (sFlt-1)/placental growth factor (PlGF) ratio is Conformite Europeenne-In Vitro Diagnostics approved as a diagnostic aid for preeclampsia, and as an aid in the short-term prediction of preeclampsia (rule out and rule in) in pregnant women with suspected preeclampsia in conjunction with other diagnostic and clinical information. In the Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia Study (PROGNOSIS), a cut-off value of 38 was derived and validated to rule out preeclampsia and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome within one week (Zeisler et al. N Engl J Med 2016;374:13–22). However, the ability of the sFlt-1/PlGF ratio to rule out preeclampsia up to four weeks in women with suspected disease has not been determined. Objectives We aimed to establish the negative predictive values (NPVs) applying the Elecsys® immunoassay sFlt-1/PlGF ratio cut-off value of 38 to rule out preeclampsia within two to four weeks after testing in women with suspected preeclampsia. Methods PROGNOSIS was a prospective, observational, multicenter study, which validated the sFlt-1/PlGF ratio cut-off value of 38 to reliably rule out preeclampsia within one week in women who had clinical signs and symptoms of the syndrome (gestational age 24w+0d–36w+6d). We performed a post-hoc analysis of the data from the validation cohort of 550 participants to determine the NPV of this ratio cut-off value to rule out preeclampsia within two, three and four weeks after testing. Results A total of 550 participants from the PROGNOSIS validation cohort were included in this analysis (median age 31years; median pre-pregnancy body mass index 26.2kg/m 2 ; median systolic blood pressure 128.0mmHg; median gestation week 31w+3d; 79 (14%) were current smokers; 418 (76%) were white/Caucasian). Of these, 98 (18%) developed preeclampsia/HELLP syndrome at some point during their pregnancy: 15 (3%) within one week; 41 (7%) within two weeks; 60 (11%) within three weeks; and 71 (13%) within four weeks. The NPV to rule out preeclampsia in women with sFlt-1/PlGF values of 38 and below within two, three and four weeks of testing was 97.9% (95% confidence interval [CI]: 96.0–99.0), 95.7% (95% CI: 93.3–97.5), and 94.3% (95% CI: 91.7–96.3), respectively (Table). Conclusions This post-hoc analysis of PROGNOSIS shows that sFlt-1/PlGF ratios of 38 and below could rule out preeclampsia for up to four weeks after testing with high NPV in women with suspicion of the syndrome.

Predictive Value of the sFlt-1 : PlGF Ratio in Women With Suspected Preeclampsia EDITORIAL COMMENT

Background Preeclampsia is defined as new onset of hypertension and proteinuria at gestational week 20 or after. However, use of these measures to predict preeclampsia before its clinical onset is unreliable, and evidence suggests that preeclampsia, eclampsia, or hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome may develop without hypertension or proteinuria being evident. Because of its unpredictability, varying clinical presentation and potential adverse outcomes, pregnant women with suspected preeclampsia require intensive monitoring or hospitalization. Beyond preeclampsia diagnosis, there is a high unmet medical need for more reliable predictive markers for preeclampsia to improve maternal and fetal outcomes and reduce unnecessary hospital admissions. An imbalance of circulating angiogenic and antiangiogenic factors, including raised soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased placental growth factor (PlGF), has been found in women diagnosed with preeclampsia and before clinical onset of the disease. The PRediction of short-term Outcome in preGNant wOmen with Suspected preeclampsIa Study (PROGNOSIS) was designed to investigate the use of the sFlt-1/PlGF ratio in the short-term prediction of preeclampsia. Methods/Design This global, multicenter, prospective, double-blind, non-interventional study aims to derive and validate cutoffs for the sFlt-1/PlGF ratio, to rule out (for 1 week) or rule in (within 4 weeks) the occurrence of preeclampsia/eclampsia/HELLP syndrome. Eligible participants are women presenting at 24 to

A new type of multibit cell for toggle type MRAM is presented. The dual-bit cell stack consists of two conventional toggle MRAM cells connected in series. These cells have the same cell geometry, anisotropy, and pinned directions but have opposite magnetic bias along the anisotropy axis directions. These oppositely biasing fields shift the write field switching window of the two cells in opposite directions along the anisotropy axis and enable the dual-bit cells to be selectively toggled. The calculated write switching current margins for the multibit cell with respect to the design and material parameters are included. The write current margin is found to be similar to the single biased low write current MRAM case. This oppositely bias scheme can be combined with the earlier multibit cell of distinct anisotropy axes approach to further enhance the density of the MRAM. This new scheme doubles the multicell bit capacity and reduces the power consumption without adding the photo-patterning steps

A woman with ophthalmic migraine was found to have bilateral cerebellar and cerebral calcifications. She progressively developed severe intracranial hypertension, with swelling of the brain and downward transtentorial and tonsillar herniation. Because steroid treatment was ineffective, the right occipital pole was resected. Histological study demonstrated meningo-cortical calcifying angiomatosis. Within 2 months, brain swelling and papilledema disappeared. Subtle signs of malabsorption led to the hypothesis of celiac disease, confirmed by jejunal biopsy. Similar cerebral histological findings have been reported in the brain of two young patients affected by epilepsy and celiac disease. The association between cerebral calcifications and celiac disease is peculiar; the pathogenetic relationship is unknown.

A new multibit magnetic random access memory (MRAM) cell of toggle switching type is presented. The multibit stack consists of multiple conventional toggle MRAM cells connected in series. These cells are identical except that their cell geometry, anisotropy, and pinned directions are oriented differently from each other. The selective write of the individual cell is achieved by using three phases of word and bit line current generating a contiguous magnetic field rotating past the easy axis of the targeted cell. Two-, four-, and six-bit toggle cell configurations are found to be feasible. This approach has the potential to greatly enhance the density of the MRAM cell for a given lithography ground rule

The natural history of 70 patients affected by low-grade astrocytomas was recorded after the histological diagnosis was obtained by serial stereotactic biopsy. Forty-three percent of these patients died within 3 years. The value of cell kinetics assessment at the time of stereotactic biopsy was investigated, and the labeling index percent may be considered the most accurate prognostic factor in these histologically homogeneous astrocytomas. It has been confirmed that the young age of patients predicts a more favorable course, but the value of this also seems to be linked to and dependent on cell kinetics. These data are discussed in view of the opportunity to perform more aggressive "cytoreductive" treatments in deep brain tumors when these indices support an expected poor prognosis.

Aim: Endoscopic ultrasound (EUS) is a valuable diagnostic tool in pancreatic diseases and its high negative predictive value (NPV) in excluding malignancies is universally recognized. Moreover, EUS with fine-needle aspiration (EUS-FNA) can significantly impact on diagnosis and management of many clinical conditions. However, there are circumstances in which EUS-FNA cannot or should not be performed. We evaluated the factors that prevented us from performing or induced us not to perform FNA. Methods: The study was conducted in a tertiary university hospital. A total of 211 patients suspected of having solid pancreatic malignancy on the basis of clinical presentation and computed tomography and/or magnetic resonance imaging was included. When FNA was withheld because not deemed necessary by the operator, the NPV of EUS was calculated. Results: In 9 patients (4.3% of the procedures), FNA was withheld because of contraindications that should have been foreseen by the referring physician. In 30 subjects, FNA was not accomplished as no lesions requiring biopsy were actually found at EUS exploration. In this group, EUS reached a NPV of 96.7% in excluding malignancy, but it reached 100% in patients without chronic pancreatitis. Conclusion: In a cohort of patients with high pre-test probability of malignancy, the high NPV of EUS was confirmed. False negative results should be expected in patients with chronic pancreatitis and they need a strict follow-up.

The magnetic recording properties of laminated media structures on hard disks are discussed, including an overview of work on this topic. The primary performance advantage of laminated media is a significant reduction in media noise. The various mechanisms proposed for this noise reduction are considered. Other issues discussed include the optimal properties for the nonmagnetic interlayers, the influence of lamination on bulk magnetic properties, soft error rate measurements, and process challenges. The most important mechanism for the improved performance that has been obtained is decoupling of the noise sources in the various layers. The optimum interlayer thickness is in the range of 20-50 AA and seems to depend on the sputtering system and process conditions used. >

La diagnosi di natura delle malformazioni vascolari influisce sulla scelta del trattamento, sia esso chirurgico, intervenzionale o conservativo. Nel caso di MAV lo studio angiografico è necessario e sufficiente, tuttavia le informazioni che la RM è in grado di fornire sulle strutture anatomiche coinvolte dalla lesione sono così importanti da giustificare un esame con RM anche ‘a posteriori», quando l'angiografia è stata eseguita in una procedura d'urgenza. La RM, in quanto esame non invasivo per eccellenza, è molto utile nei controlli dopo l'atto terapeutico, sia esso chirurgico sia esso di angiografia intervenzionale. Quando la MAV è solo durale, la RM come controllo dei casi trattati ha un valore relativo, può tuttavia dimostrare un'eventuale diminuzione di flusso. La possibilità di riconoscere un angioma venoso alla RM è importante perché frequentemente queste lesioni non sono di interesse chirurgico e, in tal caso, un esame invasivo come l'angiografia può essere risparmiato. Per le ragioni sovraesposte l'angioma cavernoso non può essere diagnosticato con certezza sulla base della sola RM. Tuttavia l'immagine caratteristica anche se non patognomonica composta da segnali di sanguinamenti avvenuti in epoche diverse e accompagnata da angiografia negativa, depone per la diagnosi di angioma cavernoso con un ragionevole margine di affidabilità. Peraltro bisogna sempre tener presente la diagnosi differenziale con un tumore maligno che abbia sanguinato. Anche in questo caso il controllo di RM, meglio con contrasto paramagnetico, rappresenta nella maggior parte dei casi il mezzo più utile e meno invasivo.

Introduction PROGNOSIS reported a negative predictive value of 99.3% (95% CI 97.9–99.9) for ruling out preeclampsia/eclampsia/HELLP syndrome within 1week using a soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio cut-off of 38 in women with suspicion of the syndrome. The sFlt-1/PlGF ratio may also help identify women likely to deliver preterm. Objectives Correlation of the sFlt-1/PlGF ratio with (a) time to delivery and (b) preterm delivery ( Methods PROGNOSIS (prospective/non-interventional) enrolled pregnant women ( ⩾ 18 years; gestational age 24wk+0d–36wk+6d at visit 1) with suspected preeclampsia (having clinical features of the syndrome). Maternal serum sFlt-1 and PlGF were measured (fully automated Elecsys ® sFlt-1 and PlGF assays; cobas e electrochemiluminescence platform; Roche Diagnostics, Mannheim, Germany) and analyzed at the study end. Assessment points: Visit 1; Visit 2 (7+2d); Visits 3, 4, and 5 (each 7 ± 2 d after previous visit); delivery; postpartum. Early and late gestational phases were defined as 24wk+0d–33wk+6d and 34wks to delivery, respectively. Cox-regression analysis was adjusted for gestational age and preeclampsia status. Results sFlt-1/PlGF ratio >38 at Visit 1 was associated with shorter time to delivery, particularly in the early gestational phase (Figure). With a median 15 (SD 11) day difference the immediate risk for delivery was higher for women with sFlt-1/PlGF ratio >38 versus ⩽ 38 (HR 2.9 [95% CI 2.5–3.5]), independent of preeclampsia status/gestational age. Women with sFlt-1/PlGF ratio ⩽ 38 had longer pregnancy duration (no preeclampsia [ n =720]: median 270 days, interquartile range [IQR] 262–279; preeclampsia [ n =91]: median 262 days, IQR 248–269) than in women with a ratio >38 (no preeclampsia [ n =159]: median 255 days, IQR 224–266; preeclampsia [ n =108]: median 251 days, IQR 232–262). These trends were consistent when the sFlt-1/PlGF ratio at any pre-delivery visit was examined (not shown). Women without preeclampsia, who had iatrogenic preterm delivery had a higher Visit 1 median sFlt-1/PlGF ratio (35.3 [IQR 6.8–104], n =171), than women with non-iatrogenic preterm delivery (8.4 [IQR 3.4–30.6], n =25) or term delivery (4.3 [IQR 2.4–10.9], n =584). For women who developed preeclampsia and delivered preterm, the median sFlt-1/PlGF ratio at Visit 1 was 121 (IQR 66.2–231, n =53). Conclusions The maternal sFlt-1/PlGF ratio gives further information on preterm delivery risk. Women with high sFlt-1/PlGF ratios (>38) should be closely monitored, regardless of preeclampsia.