Three biomarker tests to help diagnose preterm labour: a systematic review and economic evaluation.

BACKGROUND: Preterm birth may result in short- and long-term health problems for the child. Accurate diagnoses of preterm births could prevent unnecessary (or ensure appropriate) admissions into hospitals or transfers to specialist units. OBJECTIVES: The purpose of this report is to assess the test accuracy, clinical effectiveness and cost-effectiveness of the diagnostic tests PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim® Partus (Medix Biochemica, Espoo, Finland) and the Rapid Fetal Fibronectin (fFN)® 10Q Cassette Kit (Hologic, Inc., Marlborough, MA, USA) at thresholds ≠50 ng/ml [quantitative fFN (qfFN)] for women presenting with signs and symptoms of preterm labour relative to fFN at 50 ng/ml. METHODS: Systematic reviews of the published literature were conducted for diagnostic test accuracy (DTA) studies of PartoSure, Actim Partus and qfFN for predicting preterm birth, the clinical effectiveness following treatment decisions informed by test results and economic evaluations of the tests. A model-based economic evaluation was also conducted to extrapolate long-term outcomes from the results of the diagnostic tests. The model followed the structure of the model that informed the 2015 National Institute for Health and Care Excellence guidelines on preterm labour diagnosis and treatment, but with antenatal steroids use, as opposed to tocolysis, driving health outcomes. RESULTS: Twenty studies were identified evaluating DTA against the reference standard of delivery within 7 days and seven studies were identified evaluating DTA against the reference standard of delivery within 48 hours. Two studies assessed two of the index tests within the same population. One study demonstrated that depending on the threshold used, qfFN was more or less accurate than Actim Partus, whereas the other indicated little difference between PartoSure and Actim Partus. No study assessing qfFN and PartoSure in the same population was identified. The test accuracy results from the other included studies revealed a high level of uncertainty, primarily attributable to substantial methodological, clinical and statistical heterogeneity between studies. No study compared all three tests simultaneously. No clinical effectiveness studies evaluating any of the three biomarker tests were identified. One partial economic evaluation was identified for predicting preterm birth. It assessed the number needed to treat to prevent a respiratory distress syndrome case with a 'treat-all' strategy, relative to testing with qualitative fFN. Because of the lack of data, our de novo model involved the assumption that management of pregnant women fully adhered to the results of the tests. In the base-case analysis for a woman at 30 weeks' gestation, Actim Partus had lower health-care costs and fewer quality-adjusted life-years (QALYs) than qfFN at 50 ng/ml, reducing costs at a rate of £56,030 per QALY lost compared with qfFN at 50 ng/ml. PartoSure is less costly than Actim Partus while being equally effective, but this is based on diagnostic accuracy data from a small study. Treatment with qfFN at 200 ng/ml and 500 ng/ml resulted in lower cost savings per QALY lost relative to fFN at 50 ng/ml than treatment with Actim Partus. In contrast, qfFN at 10 ng/ml increased QALYs, by 0.002, and had a cost per QALY gained of £140,267 relative to fFN at 50 ng/ml. Similar qualitative results were obtained for women presenting at different gestational ages. CONCLUSION: There is a high degree of uncertainty surrounding the test accuracy and cost-effectiveness results. We are aware of four ongoing UK trials, two of which plan to enrol > 1000 participants. The results of these trials may significantly alter the findings presented here. STUDY REGISTRATION: The study is registered as PROSPERO CRD42017072696. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Infants may suffer from health problems if they are born early. If a mother has symptoms of labour before her baby is due, a test could be used to predict if the symptoms are real or a false alarm. A test could help the doctor to decide whether the mother needs treatment or to move to a specialist hospital or if she could be sent home (if it is a false alarm). Our report compares three tests [PartoSure™ (Parsagen Diagnostics Inc., Boston, MA, USA), Actim^® Partus (Medix Biochemica, Espoo, Finland) and the Fetal Fibronectin (fFN) Test (Hologic, Inc., Marlborough, MA, USA)] on how well they predict an early birth and how the costs and the long-term health outcomes of the child compare between and among tests. All the published literature reporting the accuracy of the three tests and their costs was reviewed. We developed a new cost-effectiveness model, which estimated the long-term health outcomes of the child based on the test results. Twenty of the studies reviewed looked at how good the tests were at predicting an early birth within the next 7 days, and six looked at predicting birth within 48 hours. The designs of the studies and the women taking part in the studies varied greatly. This meant that comparing the accuracy of the tests was very difficult and it would be unfair to decide which test was the best. Our model suggested no firm conclusions for the cost-effectiveness of fFN compared with Actim Partus. PartoSure appears to be less costly than Actim Partus and equally good at predicting preterm birth, but this is based on a study of very few patients. There were no data that allowed us to compare all three tests together. The accuracy of the results is uncertain, mainly because all the studies are very different. We are aware of four related UK trials that are currently ongoing that plan to include large numbers of women.

Lysyl oxidase and adipose tissue dysfunction.

BACKGROUND/OBJECTIVES: Lysyl oxidase (LOX) is an enzyme crucial for collagen fibre crosslinking and thus for fibrosis development. Fibrosis is characterised by a surplus of collagen fibre accumulation and is amongst others also a feature of obesity-associated dysfunctional adipose tissue (AT) which has been linked with type 2 diabetes. We hypothesised that in type 2 diabetes and obesity LOX expression and activity will be increased as a consequence of worsening AT dysfunction. This study aimed to provide a comprehensive characterisation of LOX in human AT. METHODS: LOX mRNA expression was analysed in omental and abdominal subcutaneous AT obtained during elective surgery from subjects with a wide range of BMI, with and without diabetes. In addition, LOX expression was studied in subcutaneous AT before and 9.5months after bariatric surgery. To study the mechanism of LOX changes, its expression and activity were assessed after either hypoxia, recombinant human leptin or glucose treatment of AT explants. In addition, LOX response to acute inflammation was tested after stimulation by a single injection of lipopolysaccharide versus saline solution (control) in healthy men, in vivo. Quantity of mRNA was measured by RT-qPCR. RESULTS: LOX expression was higher in obesity and correlated with BMI whilst, in vitro, leptin at high concentrations, as a potential feedback mechanism, suppressed its expression. Neither diabetes status, nor hyperglycaemia affected LOX. Hypoxia and lipopolysaccharide-induced acute inflammation increased LOX AT expression, latter was independent of macrophage infiltration. CONCLUSIONS: Whilst LOX may not be affected by obesity-associated complications such as diabetes, our results confirm that LOX is increased by hypoxia and inflammation as underlying mechanism for its upregulation in adipose tissue with obesity.

COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity.

Fibrosis of adipose tissue (AT) increases AT rigidity, reduces its expandability, and contributes to metabolic dysfunction. Collagen type VI, α3 (COL6A3) encodes 1 subunit of a fibrotic extracellular matrix protein highly expressed in rodent AT. Knockout of collagen VI in rodent AT led to a significant improvement in metabolic health in obese, diabetic ob/ob mice. However, it is unknown whether this collagen has the same metabolic significance in human AT. We therefore aimed to undertake a comprehensive assessment of COL6A3 in relation to human AT and obesity. Characterization of COL6A3 in human AT showed 5-fold higher expression in the stromalvascular fraction compared with adipocyte expression and significantly higher expression in subcutaneous AT (SCAT) than omental AT. In both depots, COL6A3 expression appeared to be lowered in obesity, whereas diet- and surgery-induced weight loss increased COL6A3 expression in SCAT. Leptin treatment caused a dose-dependent decrease in COL6A3 expression, although no effect was seen with insulin or glucose treatment and no difference observed in subjects with diabetes. In addition, we found that the collagen expression profile in humans differs significantly from rodents, because COL6A3 does not appear to be the predominant collagen in adipose, muscle, or liver. Our findings oppose those initially seen in rodent studies and, most importantly, demonstrate a direct regulation of COL6A3 by leptin. This highlights the importance of a paracrine leptin signaling pathway in human AT and suggests an additional mechanism by which leptin can regulate extracellular matrix composition and, with it, AT expandability.

A prospective, randomized, controlled, double-masked, multi-center clinical trial of medical adhesives for the closure of laparoscopic incisions.

STUDY OBJECTIVE: To compare LiquiBand Surgical S (LB) (Advanced Medical Solutions Ltd, Plymouth, UK) with High Viscosity Dermabond (DB) (Ethicon Inc., Kirkland, Scotland) for the closure of laparoscopic wounds. DESIGN: Prospective, multicenter, randomized, controlled trial (Canadian Task Force classification I). SETTING: Multiple district hospitals. PARTICIPANTS: A total of 433 subjects were enrolled between 2006 and 2009 at 4 investigational sites. INTERVENTIONS: In this study, LB, an octyl/butyl cyanoacrylate blend, and DB, an octyl-based cyanoacrylate, were compared for topical skin closure of laparoscopic port sites (www.clinicaltrials.gov; study identifier NCT00762905). MAIN RESULTS: High dermal apposition and cosmesis scores resulted from the use of both adhesives along with low rates of wound dehiscence and suspected infections. Masked evaluators and patients favored DB in the healing of the incisions (98.3% DB vs 93.9% LB, p < .05) and (97.2% DB vs 89.4% LB, p < .05). However, there was no difference in the overall satisfaction of the appearance of the wounds. LB was found to be significantly (p < .05) faster (LB = 32.1 seconds; DB, 50.3 seconds) and easier to use than DB, and surgical users were significantly more satisfied with using LB for wound closure. CONCLUSION: The results of this trial show the efficacy of LB for the closure of topical skin incisions; LB was significantly faster, easier to use, and resulted in greater user satisfaction compared with DB.

The mechanical properties of human adipose tissues and their relationships to the structure and composition of the extracellular matrix.

Adipose tissue (AT) expansion in obesity is characterized by cellular growth and continuous extracellular matrix (ECM) remodeling with increased fibrillar collagen deposition. It is hypothesized that the matrix can inhibit cellular expansion and lipid storage. Therefore, it is important to fully characterize the ECM's biomechanical properties and its interactions with cells. In this study, we characterize and compare the mechanical properties of human subcutaneous and omental tissues, which have different physiological functions. AT was obtained from 44 subjects undergoing surgery. Force/extension and stress/relaxation data were obtained. The effects of osmotic challenge were measured to investigate the cellular contribution to tissue mechanics. Tissue structure and its response to tensile strain were determined using nonlinear microscopy. AT showed nonlinear stress/strain characteristics of up to a 30% strain. Comparing paired subcutaneous and omental samples (n = 19), the moduli were lower in subcutaneous: initial 1.6 ± 0.8 (means ± SD) and 2.9 ± 1.5 kPa (P = 0.001), final 11.7 ± 6.4 and 32 ± 15.6 kPa (P < 0.001), respectively. The energy dissipation density was lower in subcutaneous AT (n = 13): 0.1 ± 0.1 and 0.3 ± 0.2 kPa, respectively (P = 0.006). Stress/relaxation followed a two-exponential time course. When the incubation medium was exchanged for deionized water in specimens held at 30% strain, force decreased by 31%, and the final modulus increased significantly. Nonlinear microscopy revealed collagen and elastin networks in close proximity to adipocytes and a larger-scale network of larger fiber bundles. There was considerable microscale heterogeneity in the response to strain in both cells and matrix fibers. These results suggest that subcutaneous AT has greater capacity for expansion and recovery from mechanical deformation than omental AT.

The influence of maternal age on the outcomes of pregnancies complicated by bleeding at less than 12 weeks.

The effect of maternal age on the outcome of threatened miscarriage after ultrasound has confirmed fetal heart (FH) pulsation was assessed. At a university teaching hospital, 138 women presenting with bleeding before 12 weeks' gestation were followed up until delivery or pregnancy loss. Those with multiple or ectopic pregnancy, social termination of pregnancy, assisted conception and temporary residence were excluded. Outcome measures were pregnancy loss, fetal abnormalities, preterm delivery, low birthweight and cesarean delivery. Age over 35 years was significantly associated with reduced live-birth and increased miscarriage rates. Women over 35 years of age had higher cesarean section and pregnancy loss rates than the younger women. The combination of bleeding in early pregnancy and advanced age increases risk of pregnancy loss even after ultrasound has confirmed FH pulsation.