Performance of commercial SARS-CoV-2 wild-type and Omicron BA.1 antibody assays compared with pseudovirus neutralization tests.

BACKGROUND: Commercially available ELISA-based antibody tests are used to approximate vaccination success against SARS-CoV-2 in at-risk patients, but it is unclear whether they correlate with neutralization of the Omicron variant. METHODS: 269 serum samples of a cohort of 44 non-immunosuppressed participants and 65 MTX-treated rheumatic patients taken before and after COVID-19 booster vaccinations were measured using COVID-19 antibody testing systems with wild-type and Omicron BA.1 antigens developed by three different manufacturers (surrogate virus neutralization test cPass, and binding antibody tests QuantiVac and SeraSpot), as well as with a pseudovirus neutralization test (pVNT). The pVNT was considered the gold standard for determining the presence and level of anti-SARS-CoV-2 antibodies. RESULTS: All three wild-type ELISAs showed excellent test performance compared with wild-type neutralization in pVNT. However, out of 56 samples without Omicron BA.1 neutralization in pVNT, 71.4% showed positive results in at least one and 28.6% in all three wild-type ELISAs at the manufacturer-defined cut-offs. Omicron ELISAs showed either decreased specificity (57.1% and 55.4% for binding ELISAs) or sensitivity (51.2% in cPass) compared to Omicron neutralization in pVNT. The proportion of any false positive results among all samples decreased from 26.5% before to 3.2% after booster vaccination, however binding antibody test specificities remained below 70%. CONCLUSIONS: We found a poorer test performance of new Omicron antibody test systems compared to wild-type tests in detecting neutralizing antibodies against the corresponding SARS-CoV-2 variants. Decisions for booster vaccination or passive immunization of at-risk patients should not be based solely on antibody test results.

Duloxetine in OsteoArthritis (DOA) study: effects of duloxetine on pain and function in end-stage hip and knee OA - a pragmatic enriched randomized controlled trial.

BACKGROUND: Some osteoarthritis (OA) patients experience inadequate pain relief from analgesics like acetaminophen and nonsteroidal anti-inflammatory drugs. This could be the result of experienced non-nociceptive centralized pain. Placebo-controlled randomized trials (RCT) have proven the effectiveness of duloxetine for OA and several chronic pain conditions where central sensitization (CS) is one of the key underlying pain mechanisms. OBJECTIVES: Assess the efficacy of an 8-week duloxetine treatment compared to usual care in end-stage knee and hip OA patients with a level of centralized pain. DESIGN: Pragmatic, enriched, open-label RCT. METHODS: Patients were randomized to duloxetine or to care-as-usual. Primary outcome was pain in the index joint, measured with the pain domain of the Knee injury and Osteoarthritis Outcome Score (KOOS) or the Hip disability and Osteoarthritis Outcome Score (HOOS). The intention-to-treat principle was used, with mixed-model repeated measures to analyze the effect. RESULTS: One hundred eleven patients were randomized. Nearly 44% felt much to very much better after duloxetine usage compared to 0% in the care-as-usual group (p < 0.001). The duloxetine group scored 11.3 points (95%CI: 5.8, 16.8) better on the pain domain of the KOOS/HOOS (p < 0.001). Knee patients improved significantly more than hip patients (18.7 [95%CI: 11.3, 26.1] versus 6.0 [95%CI: - 2.6, 14.5] points better). CONCLUSIONS: Adding duloxetine treatment seems to be beneficial for end-stage knee OA patients with neuropathic-like symptoms (at risk of CS). End stage Hip OA patients seem to be nonresponsive to duloxetine. TRIAL REGISTRATION: Dutch Trial Registry with number NTR 4744 (15/08/2014) and in the EudraCT database with number 2013-004313-41 .

Decision trees for optimizing the minimum detectable concentration of radioxenon detectors.

We present a novel application of machine learning techniques to optimize the design of a radiation detection system. A decision tree-based algorithm is described which greedily optimizes partitioning of energy depositions based on a minimum detectable concentration metric - appropriate for radiation measurement. We apply this method to the task of optimizing sensitivity to radioxenon decays in the presence of a high rate of radon-progeny backgrounds (i.e., assuming no physical radon removal by traditional gas separation techniques). Assuming other backgrounds are negligible, and considering sensitivity to each xenon isotope separately (neglecting interference between isotopes), we find that, in general, high resolution readout and high spatial segmentation yield little additional capability to discriminate against radon backgrounds compared to simpler detector designs.

Topical moistening of mastectomy wounds with diluted tranexamic acid to reduce bleeding: randomized clinical trial.

BACKGROUND: Topical administration of tranexamic acid (TXA) may be an alternative to intravenous administration to reduce bleeding with a lower risk of systemic adverse events. The aim of this study was to investigate whether moistening a surgical wound with TXA before closure, leaving a thin film of drug only, would reduce postoperative bleeding. METHODS: This was a two-centre, stratified, parallel-group, placebo-controlled, double-blind RCT. Patients undergoing mastectomy with or without axillary lymph node clearance were randomized 1 : 1 to moistening of wound surface before closure with either 25 mg/ml TXA or 0·9 per cent sodium chloride (placebo). The primary endpoint was postoperative bleeding as measured by drain production in the first 24 h. Secondary endpoints were early haematoma, total drain production, postoperative complications and late aspirations of seroma within 3 months. RESULTS: Between 1 January 2016 and 31 August 2018, 208 patients were randomized. Two patients were converted to a different surgical procedure at surgery, and four did not receive the intervention owing to technical error. Thus, 202 patients were included in the study (101 in the TXA and 101 in the placebo group). TXA reduced mean drain production at 24 h (110 versus 144 ml; mean difference 34 (95 per cent c.i. 8 to 60) ml, P = 0·011). One patient in the TXA group had early haematoma compared with seven in the placebo group (odds ratio (OR) 0·13 (95 per cent c.i. 0·02 to 1·07); P = 0·057). There was no significant difference in postoperative complications between TXA and placebo (13 versus 10; OR 1·11 (0·45 to 2·73), P = 0·824) or need for late seroma aspirations (79 versus 67 per cent; OR 1·83 (0·91 to 3·68), P = 0·089). CONCLUSION: Moistening the wound with TXA 25 mg/ml before closure reduces postoperative bleeding within the first 24 h in patients undergoing mastectomy. Registration number: NCT02627560 (https://clinicaltrials.gov).

ANTECEDENTES: La administración tópica de ácido tranexámico (tranexamic acid, TXA) puede ser una alternativa a la administración por vía intravenosa para reducir la hemorragia, con menor riesgo de eventos sistémicos adversos. El objetivo de este estudio fue investigar si humedecer la herida quirúrgica con TXA 25 mg/ml antes del cierre de la incisión dejando solo una fina película de fármaco, reducía la hemorragia postoperatoria. MÉTODOS: Se trata de un ensayo clínico aleatorizado, a doble ciego, controlado con placebo, de grupos paralelos, estratificado por dos centros. Las pacientes sometidas a mastectomía con/sin resección de los ganglios linfáticos axilares se asignaron al azar 1:1 para la humidificación de la superficie de la herida antes del cierre con TXA 25 mg/ml o con NaCl al 0,9% (placebo). El objetivo primario fue la hemorragia postoperatoria medida por el débito del drenaje durante las primeras 24 horas. Los objetivos secundarios fueron el desarrollo de hematoma precoz, el débito total del drenaje, las complicaciones postoperatorias y la necesidad de aspiración de un seroma tardío durante los primeros 3 meses tras la cirugía. RESULTADOS: Entre el 1 de enero de 2016 y el 31 de agosto de 2018, 208 pacientes fueron asignadas al azar. En dos pacientes tuvo que realizarse un procedimiento quirúrgico diferente durante el periodo perioperatorio y cuatro pacientes no recibieron la intervención por errores técnicos. Por lo tanto, se incluyeron 202 pacientes en el estudio (101 fueron tratadas con TXA y 101 con placebo). El TXA redujo el débito medio del drenaje a las 24 horas (110 versus 144 ml, diferencia media 34 ml, i.c. del 95%: 8 a 60 ml, P = 0,010). Se presentó un hematoma precoz en una paciente del grupo del TXA versus siete pacientes tratadas con placebo (razón de oportunidades, odds ratio, OR 0,13, i.c. del 95% 0,02-1,07, P = 0,057). No hubo diferencias significativas en las complicaciones postoperatorias entre TXA y placebo (13 versus 10, OR 1,11, i.c. del 95% 0,45-2,73, P = 0,824) o la necesidad de aspiración tardía de seromas (79,3 versus 66,6%, OR 1,83, i.c. del 95% 0,91-3,68, P = 0,089). CONCLUSIÓN: Humedecer la herida antes del cierre con TXA 25 mg/ml reduce la hemorragia postoperatoria durante las primeras 24 horas en pacientes sometidas a mastectomía.

Scalable Production of Equine Platelet Lysate for Multipotent Mesenchymal Stromal Cell Culture.

Translation of multipotent mesenchymal stromal cell (MSC)-based therapies is advancing in human and veterinary medicine. One critical issue is the in vitro culture of MSC before clinical use. Using fetal bovine serum (FBS) as supplement to the basal medium is still the gold standard for cultivation of many cell types including equine MSC. Alternatives are being explored, with substantial success using platelet lysate-supplemented media for human MSC. However, progress lags behind in the veterinary field. The aim of this study was to establish a scalable protocol for equine platelet lysate (ePL) production and to test the ePL in equine MSC culture. Whole blood was harvested into blood collection bags from 20 healthy horses. After checking sample materials for pathogen contamination, samples from 19 animals were included. Platelet concentrates were prepared using a buffy coat method. Platelets, platelet-derived growth factor BB, and transforming growth factor ß1 concentrations were increased in the concentrates compared with whole blood or serum (p < 0.05), while white blood cells were reduced (p < 0.05). The concentrates were lysed using freeze/thaw cycles, which eliminated the cells while growth factor concentrations were maintained. Donor age negatively correlated with platelet and growth factor concentrations after processing (p < 0.05). Finally, all lysates were pooled and the ePL was evaluated as culture medium supplement in comparison with FBS, using adipose-derived MSC from four unrelated donor horses. MSC proliferated well in 10% FBS as well as in 10% ePL. However, using 5 or 2.5% ePL entailed highly inconsistent proliferation or loss of proliferation, with significant differences in generation times and confluencies (p < 0.05). MSC expressed the surface antigens CD90, CD44, and CD29, but CD73 and CD105 detection was low in all culture media. Adipogenic and osteogenic differentiation led to similar results in MSC from different culture media. The buffy coat method is useful to produce equine platelet concentrate with increased platelet and reduced white blood cell content in large scales. The ePL obtained supports MSC expansion similar as FBS when used at the same concentration (10%). Further investigations into equine MSC functionality in culture with ePL should follow.

Intensive breast screening in BRCA2 mutation carriers is associated with reduced breast cancer specific and all cause mortality.

BACKGROUND: The addition of annual MRI screening to mammography has heightened optimism that intensive screening along with improved treatments may substantially improve life expectancy of women at high risk of breast cancer. However, survival data from BRCA2 mutation carriers undergoing intensive combined breast screening are scarce. METHODS: We have collated the results of screening with either annual mammography or mammography with MRI in female BRCA2 mutation carriers in Manchester and Oslo and use a Manchester control group of BRCA2 mutation carriers who had their first breast cancer diagnosed without intensive screening. RESULTS: Eighty-seven BRCA2 mutation carriers had undergone combined (n = 34) or mammography (n = 53) screening compared to 274 without such intensive screening. Ten year breast cancer specific survival was 100 % in the combined group (95 % CI 82.5-100 %) and 85.5 % (95 % CI 72.6-98.4 %) in the mammography group compared to 74.6 % (95 % CI 66.6-82.6 %) in the control group. Better survival was driven by lymph node status (negative in 67 % of screened vs 39 % of unscreened women; p < 0.001) and a significantly greater proportion of intensively screened women had invasive breast cancers <2 cm at diagnosis (74.6 % vs 50.4 %; p = 0.002). CONCLUSION: Intensive combined breast cancer screening with annual MRI and mammography appears to improve survival from breast cancer in BRCA2 mutation carriers. Data from larger groups are required to confirm the effectiveness of combined screening in BRCA2 carriers.

Duloxetine in OsteoArthritis (DOA) study: study protocol of a pragmatic open-label randomised controlled trial assessing the effect of preoperative pain treatment on postoperative outcome after total hip or knee arthroplasty.

INTRODUCTION: Residual pain is a major factor in patient dissatisfaction following total hip arthroplasty or total knee arthroplasty (THA/TKA). The proportion of patients with unfavourable long-term residual pain is high, ranging from 7% to 34%. There are studies indicating that a preoperative degree of central sensitisation (CS) is associated with poorer postoperative outcomes and residual pain. It is thus hypothesised that preoperative treatment of CS could enhance postoperative outcomes. Duloxetine has been shown to be effective for several chronic pain syndromes, including knee osteoarthritis (OA), in which CS is most likely one of the underlying pain mechanisms. This study aims to evaluate the postoperative effects of preoperative screening and targeted duloxetine treatment of CS on residual pain compared with care-as-usual. METHODS AND ANALYSIS: This multicentre, pragmatic, prospective, open-label, randomised controlled trial includes patients with idiopathic hip/knee OA who are on a waiting list for primary THA/TKA. Patients at risk for CS will be randomly allocated to the preoperative duloxetine treatment programme group or the care-as-usual control group. The primary end point is the degree of postoperative pain 6 months after THA/TKA. Secondary end points at multiple time points up to 12 months postoperatively are: pain, neuropathic pain-like symptoms, (pain) sensitisation, pain catastrophising, joint-associated problems, physical activity, health-related quality of life, depressive and anxiety symptoms, and perceived improvement. Data will be analysed on an intention-to-treat basis. ETHICS AND DISSEMINATION: The study is approved by the local Medical Ethics Committee (METc 2014/087) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013) and the Good Clinical Practice standard (GCP), and in compliance with the Medical Research Involving Human Subjects Act (WMO). TRIAL REGISTRATION NUMBER: 2013-004313-41; Pre-results.

Suspicious Prenasal Skin Thickness-to-Nasal Bone Length Ratio: Prevalence and Correlation with Other Markers in Second and Third Trimester Fetuses with Down Syndrome.

PURPOSE: To assess the prevalence and value of a suspicious prenasal skin thickness-to-nasal bone length ratio (PT/NB ratio) in comparison to other established markers in a large population of Down syndrome (DS) fetuses. MATERIALS AND METHODS: This was a retrospective study of 139 DS fetuses and 530 normal fetuses scanned after 14 + 0 weeks of gestation. To characterize diagnostic performance, we used the ROC curve approach. The presence or absence of a PT/NB ratio > 0.8 and 11 other markers were assessed in the group of DS fetuses. A correlation analysis was performed in order to investigate associations between PT/NB ratio and other markers. RESULTS: Among DS fetuses the median PT/NB ratio was 1.06 (IQR 0.729) and was significantly higher compared to normal fetuses with 0.62 (IQR 0.148), (p < 0.001). Gestational age had no influence on the PT/NB ratio. A PT/NB ratio > 0.8 had the highest prevalence of all markers with 89.2 % in the group of DS fetuses, 3 cases were negative for all markers and 3 cases were positive only for PT/NB ratio > 0.8. Marker-specific comparison between prevalences of a suspicious PT/NB ratio with respect to the presence or absence of other markers was statistically significant for hypoplastic NB and major anomalies (p < 0.05). Utilization of at least one of the following five markers was sufficient for detecting 136 out of 139 fetuses with trisomy 21: suspicious PT/NB ratio, hypoplastic NB, nuchal fold thickness, white spot, shortened femur. CONCLUSION: The PT/NB ratio is one of the most powerful indicators of DS in the second trimester. It is objective to interpret, easy to measure, and is reproducible.

[Percutaneous coronary intervention in addition to optimal medical therapy for stabile coronary artery disease - a systematic review and meta-analysis]. / Perkutane Koronarintervention zusätzlich zu optimaler medikamentöser Therapie bei stabiler koronarer Herzkrankheit. Eine systematische Übersicht und Meta-Analyse

OBJECTIVE: We evaluated the effect of percutaneous coronary interventions (PCI) in addition to optimal medical therapy in stable coronary artery disease (CAD). METHODS: A systematic literature search was conducted in the online databases MEDLINE, EMBASE etc. in June 2010, updated in February 2013 in MEDLINE and completed by a hand search. Randomized controlled trials (RCT) and systematic reviews of RCT comparing PCI vs. no PCI in stable CAD  were identified and evaluated. Results for death, myocardial infarction and angina pectoris of the RCTs using optimal medical therapy were combined with meta-analysis for relative risk (RR). The strength of the evidence was appraised based on GRADE. RESULTS: After evaluation of 7 systematic reviews and 23 RCT 4 RCTs using optimal medical therapy (Betablockers, ASS, Statins in more than 80% and ACE-Inhibitors in more than 50% of patients the study) were identified. No significant difference was found for the risks of death and of myocardial infarction between the alternatives up to 5 years after beginning the therapy. The PCI reduced the proportion of patients with angina pectoris attacks up to 3 years after beginning the therapy, RR = 0,81 (95 % CI: 0,71 to 0,92). The strength of the evidence was appraised as moderate. CONCLUSION: The use of PCI in addition to optimal medical therapy in stable CAD  may reduce the proportion of patients with angina pectoris attacks up to 3 years after beginning the therapy.

Low concentrations of sodium hypochlorite affect population dynamics in Gyrodactylus salaris (Malmberg, 1957): practical guidelines for the treatment of the Atlantic salmon, Salmo salar L. parasite.

Atlantic salmon, Salmo salar L. parr (age 1+), infected by the monogenean ectoparasite Gyrodactylus salaris (Malmberg, 1957), were exposed to chlorine (Cl)-enriched water at three different concentrations: Cllow (0-5 µg Cl L(-1) ), Clmedium (18 µg Cl L(-1) ) and Clhigh (50 µg Cl L(-1) ). There was a negative correlation between G. salaris infections and the hypochlorite concentrations added. The parasite infection was eliminated by day 6-8 and day 2-4 in the groups Clmedium and Clhigh , respectively, while inhibition of G. salaris population growth was observed in the Cllow group. An important note to this matter, however, is that the G. salaris specimens observed at day 6 in Clmedium and at day 2 in Clhigh were all considered dead by subjective judgement. No mortality in the salmon parr was observed during the first 8 days of the experiment, demonstrating that Cl has a stronger effect on G. salaris than on the salmonid host. The differences in sensitivity between the parasite and the Atlantic salmon indicate that hypochlorite has a potential use as a parasiticide with a therapeutic margin. The low-dose sensitivity may imply that Cl pollution in urban areas may pose a greater risk towards biodiversity than previously assumed.

Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients.

Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. However, its clinical significance remains to be established. In this study, the main aims were to discover whether reclassification of breast cancer into molecular subtypes provides more precise information regarding outcome compared to conventional histopathological grading and to study breast cancer-specific survival in the different molecular subtypes. Cases of breast cancer occurring in a cohort of women born between 1886 and 1928 with long-term follow-up were included in the study. Tissue microarrays were constructed from archival formalin-fixed, paraffin-embedded tissue from 909 cases. Using immunohistochemistry and in situ hybridisation as surrogates for gene expression analyses, all cases were reclassified into the following molecular subtypes: Luminal A; Luminal B (HER2-); Luminal B (HER2+); HER2 subtype; Basal phenotype; and five negative phenotype. Kaplan-Meier survival curves and Cox proportional hazards models were used in the analyses. During the first 5 years after diagnosis, there were significant differences in prognosis according to molecular subtypes with the best survival for the Luminal A subtype and the worst for HER2 and five negative phenotype. In this historic cohort of women with breast cancer, differences in breast cancer-specific survival according to subtype occur almost exclusively amongst the histopathological grade 2 tumours. From 5 years after time of diagnosis until the end of follow-up, there appears to be no difference in survival according to molecular subtype or histopathological grade.

Surgery for ruptured abdominal aortic aneurysm and early mortality in women. Risk factors and complication profile.

AIM: Repair of ruptured abdominal aortic aneurysm (rAAA) is reported to have a higher mortality in women than in men. The aim was to study whether this difference could be verified in our institution and secondary if difference in risk- and complication profiles could explain the higher 30 day mortality after surgery for rAAA in women. METHODS: During the period 1983-2009 1649 patients, 1348 men and 301 women, were operated consecutively for infrarenal abdominal aortic aneurysm (AAA); 430 patients had rAAA, 98 women and 332 men. Co-morbidities were identified from the patients' medical records. Outcome measures within 30 days were mortality, cardiac disease (heart attack, heart failure), cerebrovascular disease (stroke, TIA), renal insufficiency (serum creatinine >140 µmol/L), major amputation, bowel infarction, pancreatitis and graft related complications. RESULTS: Compared to men, women had higher 30 d mortality after surgery for rAAA (54.1% vs. 36.3%, P=0.002). Women were significantly older than men (76 years vs. 73 years, P=0.001). In the period 1995-2009 women had more autoimmune diseases than men (P=0.045). There was no significant difference between men and women for the other measured outcomes. CONCLUSION: During the period 1995-2009, autoimmune disease were more common among women than men. For all other parameters recorded, there were no differences in risk - or complication profile that could explain the higher 30 d mortality in female patients after surgery for rAAA.

Parents evaluation of the processes of care in child rehabilitation: a reliability study of the Norwegian translation of MPOC-20.

BACKGROUND: The objective was to assess the reliability of the Norwegian translation of the Canadian Measure of Processes of Care-20 (MPOC-20) questionnaire for use in child rehabilitation in Norway. MPOC-20 is a standardized questionnaire with 20 items and 5 scales that assesses to what extent parents experience that the services offered to them and their children are in line with the ideologies and principles of the family-centred service (FCS). METHODS: The translation of MPOC-20 was performed according to international standards for translation of questionnaires. A pilot study was carried out with representatives from four patient advocacy organizations. A test-retest reliability study was performed. MPOC-20 (N) was sent to the participants twice with 2- to 6-week intervals. Participants were 36 parents of 25 children aged 0-18 years. Response rate was 41.8%. RESULTS: The intraclass correlations (ICCs) for test-retest scores ranged 0.78-0.86. The internal consistency expressed as Cronbach's alpha ranged 0.62-0.93; the score was high for four of the scales and acceptable for the fifth 'Providing specific information'. These findings strongly suggest that the five scales of MPOC-20 (N) have good test-retest reliability. Average scores of each scale did not differ significantly between the first and second rating, indicating that the average scores of the ratings are stable. CONCLUSIONS: The Measure of Processes of Care-20 (N) appears to be reliable and useful in the Norwegian context, and can be recommended for evaluation of the processes of child rehabilitation(1) in Norway.

Risk of recurrence following delayed large flap reconstruction after mastectomy for breast cancer.

BACKGROUND: The aim of this retrospective matched cohort study was to evaluate the rate of recurrence among women with delayed large flap breast reconstruction after mastectomy for breast cancer. The recurrence rate among women treated at a single hospital was compared with that in an individually matched control group of women with breast cancer who did not have reconstruction after mastectomy. METHODS: Between 1982 and 2001, 125 women with previous invasive breast carcinoma underwent delayed large flap breast reconstruction with pedicled musculocutaneous or microvascular flaps (a median of 32 months after mastectomy). They were matched individually with 182 women with breast cancer who had a mastectomy but did not undergo breast reconstruction. Matching criteria were year of diagnosis, age at diagnosis and treating hospital. Medical records were evaluated until October 2007. Histopathological specimens for all included women were re-evaluated. The endpoint was locoregional or distant breast cancer recurrence. The risk of recurrent disease was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. RESULTS: Median follow-up for the entire cohort was 146 months. The reconstruction group had a 2·08 (95 per cent confidence interval 1·07 to 4·06) times higher risk of recurrent disease than the mastectomy only group. CONCLUSION: Women with breast cancer who had delayed reconstruction with a large flap in this study had a higher risk of recurrent disease than those with mastectomy alone.

The impact of first trimester screening and early fetal anomaly scan on invasive testing rates in women with advanced maternal age.

PURPOSE: To evaluate the acceptance of noninvasive screening for trisomy 13, 18, 21 and the impact on invasive testing rates in women at an age≥35 years. MATERIALS AND METHODS: In a retrospective analysis from 2003-2006 including 13 268 women≥35 years old with singleton pregnancies and 3133 invasive procedures, we evaluated the prenatal detection rate of aneuploidies in two cohorts. Group 1: advanced maternal age as sole indication, group 2: additional abnormalities and/or suspicious maternal serum parameters. In an additional analysis from 1998-2006 including 31,076 patients≥35 years, we investigated the shift in time of sonography at 11+0-13+6, 14+0-17+6 and 18+0-22+6 gestational weeks (gw). RESULTS: Among 13,268 women, 3133 invasive tests were performed with a significant decrease over time (-17%). 9% of women chose invasive testing after a normal ultrasound (group 1, n=1,267) and 14% in the case of additional markers (group 2, n=1,866). 102 cases of aneuploidy were disclosed. The proportion of detected aneuploidies was 0.86% in group 1 and 4.9% in group 2. No change in the overall detection rate (90-93%) was observed. The number of patients≥40 years increased significantly (+2.8%). There was an increase in examinations at 11+0-13+6 gw (+8%), a decrease at 14+0-17+6 gw (-10.3%) and no significant change at 18+0-22+6 gw over time. CONCLUSION: Increasing numbers of women≥35 years of age rely on the individually adjusted risk figure to make a decision about invasive testing. The application of these selective procedures can reduce the rates of invasive testing with fewer losses of normal fetuses and led to an earlier diagnosis of aneuploidies.

[Cost-effectiveness evaluation of predictive molecular diagnostics using the example of hereditary non-polyposis colorectal cancer (HNPCC)]. / Kosteneffektivitätsbewertung Prädiktiver Molekulardiagnostik am Beispiel des Hereditären Nichtpolypösen Kolorektalkarzinoms (HNPCC).

STUDY OBJECTIVE: Four different diagnostic strategies, with and without various molecular diagnostic tests, are compared and contrasted not only by years gained and the cost of therapy and diagnosis, but also by the cost-effectiveness of the diagnostic strategies. METHODOLOGY: A fictitious cohort of 100,000 people, whose genetic pre-disposition leading to the development of colorectal cancer corresponds to a representative average amongst the current population, will be studied from their 1st to their 85th year. This data will be then put through Markov models specifically developed for the study. At the end of the Markov process, it will then be possible to compile a cost-effectiveness report in regard to the various diagnostic and treatment strategies. RESULTS: A tiered diagnosis (with family case history, micro-satellite instability, molecular diagnostic diagnosis of an index person and subsequent genetic analysis of all people at risk) represents the most cost-effective method at a rate of euro 3,867 per year gained. The cost-effectiveness of a purely clinical diagnosis has a rate of euro 4,397 per year gained and is followed by the cost of direct gene testing of people at risk from families at risk at a rate of euro 6,208. The worst level of cost-effectiveness, with a rate of euro 15,705, was shown by nationwide gene screening. The incremental cost-effectiveness of Strategy IV and Strategy II is euro 124,168 per gained year. CONCLUSIONS: With the scenarios put forward we can show that a 65% reduction in gene test costs is necessary in order for a cost-effective nationwide gene screening for HNPCC to take place. The break-even level, however, depends only on a few cost-effectiveness drivers such as screening and therapy costs, proportion of HNPCC of all colorectal cancer and discounting rate. Should these changes (e.g., through a restructured medical environment), then we would see such a change in the break-even cost of a gene test and that a cost-effective nationwide gene screening could be made plausible. In a final evaluation of the use of predictive molecular diagnostics, other dimensions (such as possible psychological problems and discriminatory risks) apart from cost-effectiveness should also be included.

Automated quantitative analysis of estrogen receptor expression in breast carcinoma does not differ from expert pathologist scoring: a tissue microarray study of 3,484 cases.

BACKGROUND: Estrogen receptor (ER) expression is routinely assessed by immunohistochemistry (IHC) in breast carcinoma. Our study compares visual scoring of ER in invasive breast cancer by histopathologists to quantitation of staining using a fully automated system. MATERIALS AND METHODS: A tissue microarray was constructed from 4,049 cases (3,484 included in analysis) of invasive breast carcinoma linked to treatment and outcome information. Slides were scored independently by two pathologists and scores were dichotomised, with ER positivity recognized at a cut-off of >1% positive nuclei. The slides were scanned and analyzed with an Ariol automated system. RESULTS: Using data dichotomised as ER positive or negative, both visual and automated scores were highly consistent: there was excellent concordance between two pathologists (kappa = 0.918 (95%CI: 0.903-0.932)) and between two Ariol machines (kappa = 0.913 (95%CI: 0.897-0.928)). The prognostic significance of ER positivity was similar whether determined by pathologist or automated scoring for both the entire patient cohort and subsets of patients treated with tamoxifen alone or receiving no systemic adjuvant therapy. The optimal cut point for the automated scores using breast cancer disease-specific survival as an endpoint was >0.4% positive nuclei. The concordance between dextran-coated charcoal ER biochemical assay data and automated scores (kappa = 0.728 (95%CI: 0.69-0.75); 0.74 (95%CI: 0.71-0.77)) was similar to the concordance between biochemical assay and pathologist scores (kappa = 0.72 (95%CI: 0.70-0.75; 0.70 (95%CI: 0.67-0.72)). CONCLUSION: Fully automated quantitation of ER immunostaining yields results that do not differ from human scoring against both biochemical assay and patient outcome gold standards.

[Intrauterine treatment of incomplete fetal heart block in a mother with Sjögren syndrome]. / Intrauterine Therapie eines inkompletten AV-Blocks bei einer Mutter mit Sjögren-Syndrom.

BACKGROUND: Isolated fetal heart block is considered as an immunological disorder in the majority of cases. Mothers of affected fetuses often suffer from connective tissue disease (Sjögren syndrome or Lupus erythematodes). All of them test positive for anti-SS-A (anti Ro) and/or anti-SS-B (anti La) antibodies. Once established, third-degree congenital heart block is permanent and often requires a pacemaker. CASE: We report on a pregnancy in a mother with Sjögren syndrome which was complicated by the development of incomplete fetal heart block, diagnosed by pulsed wave Doppler echocardiography. We started oral dexamethasone treatment to reduce immune-mediated fetal cardiac damage and to prevent complications like hydrops fetalis. CONCLUSION: Detection of isolated fetal heart block is possible with pulsed Doppler sonography, but there are no clear recommendations for treatment.