A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (SpA) is a chronic inflammatory disease characterized by back pain and stiffness. The objective of this study was to determine whether golimumab is superior to placebo in patients with nonradiographic axial SpA. METHODS: This phase III, double-blind, randomized, placebo-controlled trial was performed to evaluate subcutaneous golimumab (50 mg) versus placebo in patients ages ≥18 years to ≤45 years who had active nonradiographic axial SpA according to the Assessment of SpondyloArthritis international Society (ASAS) criteria for ≤5 years since diagnosis, high disease activity, and an inadequate response to or intolerance of nonsteroidal antiinflammatory drugs. Patients were randomized 1:1 to receive golimumab or placebo subcutaneously every 4 weeks. The primary end point was 20% improvement according to the ASAS criteria (ASAS20) at week 16. Key secondary end points were an ASAS40 response, ASAS partial remission, 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and change in the Spondyloarthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) index for sacroiliac (SI) joint inflammation (SPARCC score). RESULTS: Of the 198 patients randomized, 197 were treated (97 received golimumab, and 100 received placebo). The mean age of the patients was 31 years, and 57.1% were male. At baseline, the mean ± SD BASDAI was 6.5 ± 1.5, the mean ± SD ASDAS was 3.5 ± 0.9, and the mean ± SD SPARCC score was 11.3 ± 14.0. The primary end point, an ASAS20 response, was achieved by significantly more patients in the golimumab group compared with the placebo group (71.1% versus 40.0%; P < 0.0001). An ASAS40 response was also achieved by significantly more patients in the golimumab group compared with the placebo group (56.7% versus 23.0%; P < 0.0001). The incidence of adverse events did not differ meaningfully between groups. CONCLUSION: Patients with active nonradiographic axial SpA treated with golimumab had significantly greater improvement in symptoms compared with patients treated with placebo. Golimumab was well tolerated and had a favorable risk/benefit profile.

Effects of prolonged mechanical ventilation with a closed suction system on endotracheal tube resistance and its reversibility by a closed suction cleaning system.

The study objective was to evaluate endotracheal tubes (ETT) from extubated adult patients and compare them to new, unused, size-matched control tubes for changes in inspiratory resistance (Rinsp) and peak inspiratory pressure (PIP) before and immediately after suctioning with the Airway Medix Closed Suction System (AMCSS) (Biovo Technologies, 2013 Tel Aviv, Israel). Sixteen ETTs were recovered from predominantly medical patients who had required intubation and mechanical ventilation for more than 12 hours. ETTs were evaluated within 4.5 hours of extubation. Readings were taken during square wave flow, at rates of 40 and 60 l/minute. Cleaning of extubated ETTs using the AMCSS was able to restore them to almost original conditions in terms of Rinsp and PIP. The examined ETTs included tubes of various sizes ranging from internal diameter (ID) 7 to 8.5 mm and intubation periods ranging from 12 hours to 21 days. The mean Rinsp for the used and uncleaned ETTs was equivalent to 275% of the Rinsp of sized-matched new and unused ETTs. For 8 mm ID ETTs this was comparable to a measured Rinsp of a 5 mm tube. Following a single cleaning episode with the AMCSS, Rinsp decreased, regaining an effective ETT ID of a 7.5 to 8 mm tube. A single suctioning episode with this device resulted in a significant reduction in Rinsp, virtually restoring original flow variable values. The AMCSS represents a novel technology in closed suction systems, designed to achieve more effective inner lumen cleaning in prolonged mechanical ventilation.

The impact of treatment with risperidone long-acting injection on the Belgian healthcare system: results from a budget impact model.

Substantial evidence from randomised clinical trials has demonstrated that long-acting risperidone (RLAI) is efficacious and well tolerated in patients with schizophrenia. Recently, a long-term naturalistic study of treatment practices in Belgium, the electronic Schizophrenia Treatment Adherence Registry (e-STAR), reported that treatment with RLAI is associated with improvements in adherence and long-term outcomes. The present report describes the results of a budget impact model that analysed the Belgian e-STAR data, together with other available data, over a 3-year time horizon, in order to establish the potential impact of treatment with RLAI on total healthcare costs in Belgium.The model framework combined medical resource utilisation with costs of the population of interest in order to quantify the costs, and cost offsets, of RLAI treatment. For the purpose of this budget impact model, it was assumed that among patients who would discontinue their previous antipsychotic medication, 6.7% of patients would be switched to RLAI. The overall cost savings to the Belgian healthcare system were calculated to be 2.3 million Euros in Year 1, 3.7 million Euros in Year 2 and 4.4 million Euros in Year 3. The majority of these cost-savings resulted from the substantial reduction in hospitalisation costs associated with RLAI treatment. This report indicates that improvements in adherence and long-term outcomes previously demonstrated for RLAI treatment in Belgium may result in substantial cost benefits to the country's healthcare system.

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.

OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Factors associated with failure to correct the international normalised ratio following fresh frozen plasma administration among patients treated for warfarin-related major bleeding. An analysis of electronic health records.

This study assessed the frequency and factors associated with failure to correct international normalised ratio (INR) in patients administered fresh frozen plasma (FFP) for warfarin-related major bleeding. This retrospective database analysis used electronic health records from an integrated health system. Patients who received FFP between 01/01/2004 and 01/31/2010, and who met the following criteria were selected: major haemorrhage diagnosis the day before to the day after initial FFP administration; INR ≥2 on the day before or the day of FFP and another INR result available; warfarin prescription within 90 days. INR correction (defined as INR ≤1.3) was evaluated at the last available test up to one day following FFP. A total of 414 patients met selection criteria (mean age 75 years, 53% male, mean Charlson score 2.5). Patients presented with gastrointestinal bleeding (58%), intracranial haemorrhage (38%) and other bleed types (4%). The INR of 67% of patients remained uncorrected at the last available test up to one day following receipt of FFP. In logistic regression analysis, the INR of patients who were older, those with a Charlson score of 4 or greater, and those with non-ICH bleeds (odds ratio vs. intracranial bleeding 0.48; 95% confidence interval 0.31-0.76) were more likely to remain uncorrected within one day following FFP administration. In an alternative definition of correction, (INR ≤1.5), 39% of patients' INRs remained uncorrected. For a substantial proportion of patients, the INRs remain inadequately or uncorrected following FFP administration, with estimates varying depending on the INR threshold used.

Failure to correct International Normalized Ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records.

BACKGROUND: Delayed correction of blood clotting times as measured by the International Normalized Ratio (INR) is associated with adverse outcomes among certain patients with warfarin-related major bleeding. However, there are limited data on the association between INR correction and mortality. OBJECTIVE: To assess factors associated with 30-day mortality and time to death in patients receiving fresh frozen plasma (FFP) for warfarin-associated major bleeding. METHODS: A retrospective database analysis was undertaken with electronic health record data from a large integrated health system. Patients met the following criteria: major hemorrhage diagnosis; INR ≥ 2 on the day before or day of receipt of FFP; and prescription fill for warfarin within 90 days. INR correction (defined as INR ≤ 1.3) was evaluated at the last available test 1 day following the start of FFP administration. Kaplan-Meier curves and Cox proportional hazards models were constructed to assess mortality. RESULTS: Four hundred and five patients met the selection criteria (mean age of 75 years, 54% male), and 67% remained uncorrected at 1 day following the start of FFP administration. Among all patients, 11% died within 30 days of hospital admission. An uncorrected INR was not associated with a higher risk of 30-day mortality for patients overall, but was statistically significant for the subgroup with intracranial hemorrhage (ICH) (adjusted odds ratio 2.55; 95% confidence interval 1.04-6.28). CONCLUSIONS: Among the subgroup of major bleeding patients with warfarin-associated ICH, those not correcting to either INR ≤ 1.3 or INR ≤ 1.5 with the use of FFP have an increased rate of mortality at 30 days.

The association between cytomegalovirus immune globulin and long-term recipient and graft survival following liver transplantation.

The association between cytomegalovirus (CMV) immune globulin (CMVIG) and long-term clinical outcomes has not been well defined. We examined the association between CMVIG and long-term recipient and graft survival in liver transplant recipients. Data were from the Scientific Registry of Transplant Recipients and included recipients transplanted between January 1995 and October 2008; follow-up was through March 2009. All recipients≤80 years of age with primary, single-organ liver transplants, given CMVIG with (n=2350) or without antivirals (n=455), antivirals without CMVIG (n = 32,939), or no CMV prophylaxis (n=28,508) before discharge were included. Kaplan-Meier analysis was used to examine rates of acute rejection (AR), graft loss, and death, over 7 years post transplantation. The adjusted risk of AR, graft loss, and death associated with CMVIG with and without antivirals vs. no prophylaxis was estimated using the Cox proportional hazards regression. In the univariate analysis, CMVIG, with and without antivirals, was associated with increased AR rates, but decreased mortality; CMVIG with antivirals was also associated with decreased graft loss compared with no prophylaxis. From the multivariable model, CMVIG with antivirals was associated with increased risk for AR, but decreased risk for graft loss and death; after adjustment, the association between CMVIG alone and mortality was not significant. CMVIG with antivirals is associated with increased risk of AR but greater long-term patient and graft survival after liver transplantation.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery.

Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate-P®) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg⁻¹ VWF: RCo. Median plasma levels, half-life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time-concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL⁻¹ (range, 6-124); with a mean change from baseline >100 IU dL⁻¹ immediately after the infusion, decreasing to 10 IU dL⁻¹ at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL⁻¹ per IU kg⁻¹, for VWF:Ag 2.3 IU dL⁻¹ kg⁻¹ and for FVIII:C was 2.7 IU dL⁻¹ per IU kg⁻¹. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra-individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri-operative infusions.

Economic models in type 2 diabetes.

OBJECTIVE: To identify and critically appraise cost-effectiveness models developed to evaluate type 2 diabetes (T2D) treatments and to assess which types of treatment effects they capture. RESEARCH DESIGN AND METHODS: A systematic search was performed in MEDLINE, EMBASE, Centre for Reviews and Dissemination databases at the University of York, and Health Economic Evaluation Database for the period to September 2008. The websites of Health Technology Assessment (HTA) bodies in different countries were also screened for relevant models. For each of the identified original models, details of the structure, data in- and outputs were extracted and the overall quality of the model in terms of the combination of structure, assumptions and data inputs were appraised using published criteria. RESULTS: Seventy-eight articles and 41 HTAs reporting relevant economic evaluations were identified. There were ten models with multiple publications, and a further ten models with one associated publication. The critical review demonstrated that most had the same fundamental structure, used similar micro-simulation techniques and were based on the same key data sources. However, the process for identification of relevant data and their synthesis, and the selection of outcomes lacked transparency. The models differed according to the extent and type of interventions they evaluated and which diabetes complications and treatment-related adverse events were captured. For example, just one model incorporated changes in patient weight, despite the fact that weight gain can be a side-effect of some treatments, and weight loss a potential benefit of others. CONCLUSIONS: Whilst many economic models exist in T2D, most share common features such as the model type. Identified shortcomings are lack of transparency in data identification and evidence synthesis as well as the selection of the modelled outcomes. Future models should aim to include all relevant treatment outcomes, whether these relate to effects on underlying diabetes and its complications or to short- or long-term side effects of treatment.

Diagnostic precision of Doppler flow echocardiography in fetuses at risk for atrioventricular block.

OBJECTIVE: To investigate the diagnostic precision of three Doppler methods in their ability to predict postnatal first-degree atrioventricular (AV) block. METHODS: This was a prospective, observational study carried out from December 1999 to March 2008, including 95 fetuses of anti-SSA/Ro positive mothers undergoing weekly fetal echocardiograms at 18-24 weeks' gestation. Doppler-derived AV time intervals for left ventricular inflow (MV), inflow and outflow (MV-Ao) and superior vena cava a-wave to aortic flow (SVC-Ao) were compared with the PR interval on postnatal electrocardiography. Reference values for MV intervals were established from 102 healthy fetuses, with previously published reference ranges used for the two other methods. Bayesian and receiver-operating characteristics (ROC) curve analyses were performed. RESULTS: The prevalence of first-degree AV block at birth was 13.8%. Using a cut-off at the upper 95% confidence limit, MV-Ao and SVC-Ao time intervals had a sensitivity of 91.7%, and negative predictive value and negative likelihood ratio of 98.4% and 0.10, respectively. The corresponding positive predictive value/positive likelihood ratio for MV-Ao and SVC-Ao were 42.3%/4.5 and 47.8%/5.7, respectively. The areas under the ROC curve (AUC) for MV-Ao and SVC-Ao were 0.87 and 0.89, respectively (both P < 0.001), with generated cut-offs for abnormal AV time intervals at 134-138 and 132-138 ms. MV time intervals using a cut-off at the upper 95% confidence limit had a sensitivity of just 50% and an AUC of 0.74 (P < 0.01). CONCLUSION: The MV-Ao and SVC-Ao Doppler methods make it possible to identify nearly all fetuses with first-degree AV block at birth and to exclude conduction disturbances in the case of a normal AV time measurement but at the cost of a positive predictive value of 50%.

Clinical feasibility of a magnetic resonance tracking system to guide the position of the scan plane during physiologic joint motion.

PURPOSE: Unrestricted physiologic joint motion results in multidirectional displacement of the anatomic structures. When performing real-time magnetic resonance (MR) imaging of such a joint motion, continuous adjustment of the scan plane position may be required. The purpose of this study was to evaluate the clinical feasibility of a method to guide the scan plane position during dynamic-motion MR imaging of freely moving joints. MATERIALS AND METHODS: The location of a small tracker device (dedicated hardware) placed on the patient's skin overlying a joint was determined by an ultrashort MR sequence and used to automatically adjust the scan plane position prior to each dynamic-motion MR image. Using a vertically open MR unit, this MR tracking system was applied in ten dynamic-motion MR examinations to evaluate flexion/extension manoeuvres in the weight-bearing knee joint, and in ten dynamic-motion MR examinations of the shoulder joint to evaluate manoeuvres such as internal/external rotation of the humerus, stress testing of the glenohumeral joint and abduction/adduction manoeuvres. Average number of manoeuvre repetitions, total number of images and percentage of useful images per manoeuvre were calculated. Imaging time per scan plane for each manoeuvre was recorded. RESULTS: Average repetition of manoeuvres varied between 1.6 and 5.8, with an average number of 7 to 18 images per manoeuvre. Average percentage of useful images varied between 61% and 89%. Total imaging time per scan plane ranged between 1 min 10 s and 4 min 51 s. CONCLUSIONS: The MR tracking system to guide the slice position for each consecutive dynamic-motion MR image of the freely but slowly moving shoulder or knee joint was feasible for clinical use, providing a high percentage of useful images for each manoeuvre within a clinically acceptable time frame.

Anti-Ro52/SSA antibody-exposed fetuses with prolonged atrioventricular time intervals show signs of decreased cardiac performance.

OBJECTIVE: To investigate if anti-Ro/SSA antibody-exposed fetuses with prolonged atrioventricular (AV) time intervals also have prolongation of the isovolumetric contraction time (ICT). METHODS: Seventy-eight anti-Ro/SSA (including 70 anti-Ro52) antibody-exposed fetuses at risk for congenital heart block (CHB) were followed weekly, between 18 and 24 weeks of gestation, with two Doppler echocardiographic methods designed to detect signs of first-degree AV block. One of these AV time measurements, using hemodynamic events from the mitral valve and aortic outflow as indirect markers of atrial and ventricular depolarization (MV-Ao), was also used to calculate a time interval representing an early phase of systolic cardiac performance, i.e. the ICT. Two hundred and eighty-four women with normal pregnancies served as controls for AV time intervals and another 106 were used to establish an ICT reference range. RESULTS: Strong positive relationships were found between ICT and MV-Ao time intervals (r = 0.91, P < 0.001), as well as between ICT and time intervals obtained from the superior vena cava and aorta (r = 0.85, P < 0.001). The ICT was estimated to contribute more than 50% of the total AV time prolongation. Abnormal AV time and ICT intervals were only seen in anti-Ro52 positive pregnancies. CONCLUSIONS: The ICT is an important contributor to prolongation of AV time intervals. This observation suggests that anti-Ro52/SSA antibody-exposed fetal hearts have not only disturbed electrical conduction but also decreased mechanical performance. Moreover, our findings have implications for the interpretation of AV time intervals used for surveillance of fetuses at risk for developing CHB.

Evaluation of the efficacy and safety of etoricoxib compared with naproxen in two, 138-week randomised studies of patients with osteoarthritis.

OBJECTIVES: To assess the efficacy and safety of etoricoxib 60 mg once daily and naproxen 500 mg twice daily over a 138-week treatment period in patients with osteoarthritis (OA). METHODS: Two 1-year randomised, double blind, parallel group two-part base studies (part I 12 weeks; part II 40 weeks), followed by an 86-week extension, in patients with OA (hip or knee) were conducted at 80 clinical centres (19 countries). The studies had identical designs. Patients taking placebo in part I received etoricoxib or naproxen (1:1 ratio) in part II and the extension; patients taking etoricoxib or naproxen in part I continued to receive the same treatment throughout the entire length of the studies. Co-primary efficacy end points were patient global assessment of disease status, and WOMAC questionnaire pain subscale and physical function subscale (100 mm VAS). Efficacy over 138 weeks was assessed by graphical analysis. Safety was assessed by observation of adverse experiences and laboratory and physical evaluations. RESULTS: 997 patients entered (615 completed) the base studies. Of these patients, 463 patients entered the extensions. A total of 161 and 152 patients in the etoricoxib and naproxen groups, respectively, completed 138 treatment weeks. Etoricoxib and naproxen showed similar efficacy throughout the 138 weeks of treatment. For etoricoxib and naproxen, respectively, WOMAC pain assessments were 67 and 67 mm (baseline); 28 and 29 mm (1 year), and 34 and 33 mm (138 weeks). Results for the other efficacy end points were similar to those seen with the WOMAC pain assessments. Both etoricoxib and naproxen were generally well tolerated. CONCLUSION: Both etoricoxib and naproxen demonstrated long-term clinical efficacy for the treatment of OA. Etoricoxib and naproxen were generally well tolerated.

Doppler echocardiographic and electrocardiographic atrioventricular time intervals in newborn infants: evaluation of techniques for surveillance of fetuses at risk for congenital heart block.

OBJECTIVE: To evaluate one novel and two previously reported Doppler flow velocimetric techniques to estimate atrioventricular (AV) time intervals, suggested to be useful for early identification of fetuses at risk for congenital heart block. METHODS: In 22 newborn infants, Doppler tracings were obtained from the mitral valve/aortic outflow and the superior vena cava/ascending aorta, as an ECG was recorded simultaneously. AV time intervals were measured using the onsets of the mitral A-wave/aortic outflow (MV-Ao), superior vena cava a-wave/aortic flow (SVC-Ao), and mitral A-wave/mitral valve closure (MV) as indirect markers of electrical atrial/ventricular activation. RESULTS: Close positive linear relationships to the electrocardiographic PR interval were demonstrated for the MV-Ao (r = 0.82, S(y/x) = 7.4 ms), SVC-Ao (r = 0.85, S(y/x) = 6.8 ms), and MV (r = 0.92, S(y/x) = 3.8 ms) approaches. Both techniques using the aortic flow to indicate ventricular activation overestimated the PR interval: the MV-Ao by + 32 +/- 7.7 ms (mean +/- SD) and the SVC-Ao approach by + 22 +/- 7.0 ms. The new MV approach using mitral closure for the same purpose did not overestimate the PR interval, but there was a trend towards underestimation of the PR intervals as time intervals increased. CONCLUSIONS: When systematic differences between echocardiographic and electrocardiographic AV time intervals are compensated for, all three techniques are useful to get indirect estimates of the PR interval. As MV recordings only need insonation of a single valve, and are thus easier to obtain, this technique may be of value as a first screening method to identify fetuses in need for further surveillance. In cases with AV time prolongation the SVC-Ao method seems superior.

Routine ultrasound examination at 12 or 18 gestational weeks for prenatal detection of major congenital heart malformations? A randomised controlled trial comprising 36,299 fetuses.

OBJECTIVE: To compare the rate of prenatal diagnosis of heart malformations between two policies of screening for heart malformations. DESIGN: Randomised controlled trial. SETTING: Six university hospitals, two district general hospitals. SAMPLE: A total of 39 572 unselected pregnancies randomised to either policy. METHODS: The 12-week policy implied one routine scan at 12 weeks including measurement of nuchal translucency (NT), and the 18-week policy implied one routine scan at 18 weeks. Fetal anatomy was scrutinised using the same check-list in both groups, and in both groups, indications for fetal echocardiography were ultrasound findings of any fetal anomaly, including abnormal four-chamber view, or other risk factors for heart malformation. In the 12-week scan group, NT >or=3.5 mm was also an indication for fetal echocardiography. MAIN OUTCOME MEASURE: Prenatal diagnosis of major congenital heart malformation. RESULTS: In the 12-week scan group, 7 (11%) of 61 major heart malformations were prenatally diagnosed versus 9 (15%) of 60 in the 18-week scan group (P= 0.60). In four (6.6%) women in the 12-week scan group, the routine scan was the starting point for investigations resulting in a prenatal diagnosis versus in 9 (15%) women in the 18-week scan group (P=0.15). The diagnosis was made

Is measurement of nuchal translucency thickness a useful screening tool for heart defects? A study of 16,383 fetuses.

OBJECTIVE: To determine the performance of nuchal translucency thickness (NT) measurement as a screening method for congenital heart defects (CHD) among fetuses with normal karyotype. METHODS: An NT measurement was made in 16 383 consecutive euploid fetuses derived from an unselected pregnant population. The cut-offs for increased risk of heart defects, chosen a priori and tested prospectively, were: NT >or= 95th centile for crown-rump length, NT >or= 3 mm, and NT >or= 3.5 mm. The sensitivity and false-positive rate (FPR; 1 minus specificity) of the risk cut-offs and their positive and negative likelihood ratios (+LR and -LR) with regard to CHD were calculated. RESULTS: Among the 16 383 fetuses with an NT measurement there were 127 cases with a diagnosis of heart defect confirmed by cardiac investigations after birth or at autopsy. Of these, 55 defects were defined as major, of which 52 were isolated (no other defects or chromosomal aberrations), corresponding to a prevalence of major heart defects in chromosomally normal fetuses/newborns of 3.3/1000. The sensitivity, FPR, +LR and -LR for NT >or= 95th centile with regard to an isolated major heart defect were: 13.5%, 2.6%, 5.2 and 0.9, respectively. For NT >or= 3.0 mm these values were: 9.6%, 0.8%, 12.0 and 0.9, and for NT >or= 3.5 mm they were: 5.8%, 0.3%, 19.3 and 0.9. CONCLUSIONS: NT measurement is a poor screening method for isolated major CHD. A method with a much higher detection rate and with a reasonably low FPR is needed. However, increased NT indicates increased risk of fetal heart defect, and women carrying fetuses with increased NT should be offered fetal echocardiography in the second trimester.

[Clinical and morphological aspects of shigellosis flexneri in patients with an aggravated premorbid state]. / Kliniko-morfologicheskie osobennosti shigelleza fleksnera u bol'nykh s otiagoshchennym premorbidnym fonom.

The analysis of 10 fatal outcomes in patients with acute shigellosis during the period of 1999-2000 made it possible to find out that most of deceased shigellosis patients belonged to the group inclined to alcohol abuse and having initial alimentary disturbances. In 6 cases of acute shigellosis with fatal outcome the causative agent was S. flexneri 2a, in 2 cases--S. flexneri 3a, in 1--S. flexneri 4b. The main cause of fatal outcomes was accompanying double pneumonia. Lesions of the intestinal tract in deceased shigellosis patients were of destructive character, resulting, in a number of cases, in serous and perforative peritonitis.

Detection of differentially expressed genes in mouse lung adenocarcinomas.

Increasing evidence suggests that altered gene expression is associated with the induction and maintenance of malignancy in various organs including mouse lung adenocarcinomas. A competitive cDNA library screening (CCLS) was used to examine gene expression in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung adenocarcinomas from (C3H/HeJ x A/J])F1 mice. Comparisons of RNA expression in lung adenocarcinomas to those of normal surrounding lung tissue revealed altered expression in 220 clones from more than 50,000 clones screened. Fifty clones were selected for quantitative reverse transcriptase-polymerase chain reaction (PCR) analysis to verify altered expression. PCR primers were designed based on partial sequence analysis of the clones. Twenty-two clones were found to be differentially expressed in lung adenocarcinomas compared with normal lungs. GenBank database analysis showed that 14 of the 22 clones were homologous with known genes, whereas 8 clones contained novel sequences. Thirteen clones were down regulated in tumors compared to normal lung tissues, and 9 were overexpressed. The clones underexpressed or absent include adipocyte p27, carbonic anhydrase III, carbonyl reductase, cytochrome CYP2E1, skelemin, myosin, major urinary protein, and contrapsin. Overexpressed clones include Bruton's tyrosine kinase, cyclin D3, poly(A)-binding protein, alpha-fetoprotein, transferrin, and mouse B2 family repetitive sequence. Further examination of biologic implications of the differentially expressed genes in lung adenocarcinomas is necessary to understand their role(s) in mouse lung carcinogenesis.