Commentary on a combined approach to the problem of developing biomarkers for the prediction of spontaneous preterm labor that leads to preterm birth.

INTRODUCTION: Globally, preterm birth has replaced congenital malformation as the major cause of perinatal mortality and morbidity. The reduced rate of congenital malformation was not achieved through a single biophysical or biochemical marker at a specific gestational age, but rather through a combination of clinical, biophysical and biochemical markers at different gestational ages. Since the aetiology of spontaneous preterm birth is also multifactorial, it is unlikely that a single biomarker test, at a specific gestational age will emerge as the definitive predictive test. METHODS: The Biomarkers Group of PREBIC, comprising clinicians, basic scientists and other experts in the field, with a particular interest in preterm birth have produced this commentary with short, medium and long-term aims: i) to alert clinicians to the advances that are being made in the prediction of spontaneous preterm birth; ii) to encourage clinicians and scientists to continue their efforts in this field, and not to be disheartened or nihilistic because of a perceived lack of progress and iii) to enable development of novel interventions that can reduce the mortality and morbidity associated with preterm birth. RESULTS: Using language that we hope is clear to practising clinicians, we have identified 11 Sections in which there exists the potential, feasibility and capability of technologies for candidate biomarkers in the prediction of spontaneous preterm birth and how current limitations to this research might be circumvented. DISCUSSION: The combination of biophysical, biochemical, immunological, microbiological, fetal cell, exosomal, or cell free RNA at different gestational ages, integrated as part of a multivariable predictor model may be necessary to advance our attempts to predict sPTL and PTB. This will require systems biological data using "omics" data and artificial intelligence/machine learning to manage the data appropriately. The ultimate goal is to reduce the mortality and morbidity associated with preterm birth.

Guía de actuación para el manejo de la infección por COVID-19 durante en el embarazo / A clinical management protocol for COVID-19 infection in pregnant women

La infección causada por el nuevo coronavirus SARS-CoV-2 (COVID-19) representa actualmente una de las mayores emergencias sanitarias a nivel mundial. La aparición de una nueva infección potencialmente grave y la situación de pandemia actual ha implicado importantes ajustes en la práctica clínica en medicina materno-fetal. Aunque no parece existir una mayor afectación o susceptibilidad al virus de las mujeres embarazadas respecto la población general, existen aspectos específicos ligados a la gestación que deben tenerse en cuenta de cara al diagnóstico y manejo de la COVID-19 en pacientes embarazadas. En el siguiente documento se exponen las recomendaciones y el protocolo de actuación ante la infección por COVID-19 durante el embarazo desarrollado en nuestro centro, basado en la evidencia científica disponible hasta la fecha y las principales recomendaciones internacionales

The severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) disease (COVID-19) has caused a large global outbreak and has had a major impact on health systems and societies worldwide. The generation of knowledge about the disease has occurred almost as fast as its global expansion. Very few studies have reported on the effects of the infection on maternal health, since its onset. The mother and foetus do not seem to be at particularly high risk. Nevertheless, obstetrics and maternal-foetal medicine practice have made profound changes in order to adapt to the pandemic. In addition, there are aspects specific to COVID-19 and gestation that should be known by specialists. In this review an evidenced-based protocol is presented for the management of COVID-19 in pregnancy

[A clinical management protocol for COVID-19 infection in pregnant women]. / Guía de actuación para el manejo de la infección por COVID-19 durante en el embarazo.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has caused a large global outbreak and has had a major impact on health systems and societies worldwide. The generation of knowledge about the disease has occurred almost as fast as its global expansion. Very few studies have reported on the effects of the infection on maternal health, since its onset. The mother and foetus do not seem to be at particularly high risk. Nevertheless, obstetrics and maternal-foetal medicine practice have made profound changes in order to adapt to the pandemic. In addition, there are aspects specific to COVID-19 and gestation that should be known by specialists. In this review an evidenced-based protocol is presented for the management of COVID-19 in pregnancy.

Latencia al parto tras cerclaje de emergencia en gestación múltiple / Latency to delivery after emergency physical-examination indicated cerclage in twin pregnancy

Introducción: Las guías clínicas actuales recomiendan el uso del cerclaje de emergencia (CE) como tratamiento de la insuficiencia cervical con exposición de membranas en gestaciones únicas. Sin embargo, el CE en gestación múltiple es tema de controversia dado que no existen ensayos clínicos randomizados que demuestren su eficacia. Algunos estudios retrospectivos sugieren que el CE también podría prolongar la gestación en embarazos múltiples. El objetivo de nuestro estudio es evaluar los resultados de las gestaciones múltiples que se sometieron a un CE en nuestro centro. Materiales y métodos: Se diseñó un estudio retrospectivo que incluyó los CE realizados en gestaciones gemelares en nuestro centro entre 2007-2016. No fueron tributarias de CE gestaciones con malformaciones fetales, monocoriales-monoamnióticas, triple o superior y finalizaciones activas de la gestación. Variables primarias: latencia al parto espontáneo y edad gestacional al parto. Variables secundarias: mortalidad neonatal, ingreso en UCI neonatal, rotura prematura de membranas pretérmino, corioamnionitis y fallo del cerclaje. Resultados. El estudio incluyó 17 pacientes. La edad gestacional mediana (rango intercuartil) al parto fue de 27,1 (24,5-32,3) semanas y la latencia mediana (rango intercuartil) al parto fue de 43 (21-64) días. Hubo 4/17 (23,5%) casos de parto antes de las 24 semanas de gestación y 2/26 (7,7%) de muerte neonatal. Discusión: Estos resultados muestran que la latencia al parto después del CE en gestación múltiple es remarcable, por lo que podría ser considerado como una opción terapéutica. Sin embargo, se requiere evidencia basada en estudios randomizados para hacer una recomendación firme

Introduction: Current guidelines support the use of physical-examination indicated cerclage (PEIC) as a treatment for cervical insufficiency and membrane exposure in single pregnancies. However, PEIC in twin pregnancies is a controversial issue as no data from random clinical trial are available to demonstrate its efficacy. Few studies suggest that PEIC may prolong pregnancy also in twin pregnancies. The aim of this study was to evaluate the results of twin pregnancies that underwent a PEIC in our health centre. Material and methods: A retrospective review was performed on women that underwent a PEIC from 2007-2016 in our centre. Women were not eligible if they were carrying foetuses with major foetal anomalies, more than two foetuses or monochorionic-monoamniotic pregnancies, or three or more foetuses or requesting an elective termination of pregnancy. Primary outcomes: latency to spontaneous delivery and gestational age (GA) at delivery. Secondary outcomes: neonatal mortality and Neonatal Intensive Care Unit admission, preterm premature rupture of membranes (PPROM), chorioamnionitis and cerclage displacement. Results: The study included a total of 17 women. The median (inter-quartile range) gestational age at delivery was 27.1 (24.5-32.3) weeks, and median (inter-quartile range) latency, from cervical cerclage to delivery, was 43 (21-64) days. There were 4/17 (23.5%) cases of delivery before 24 weeks of pregnancy, and 2/26 (7.7%) cases of neonatal death. Discussion: These results suggest that latency to delivery after PEIC in twins is remarkable. Therefore, it could be considered as an optional management. Nevertheless, evidence based on random clinical trial is required to make firm recommendations on its formal use

Class I and Class II small leucine-rich proteoglycans in human cutaneous pacinian corpuscles.

Pacinian corpuscles are onion bulb-like multilayered mechanoreceptors that consist of a complicated structure of axon terminals, Schwann related cells (inner core), endoneural related cells (intermediate layer) and perineurial related cells (outer core-capsule). The cells forming those compartments are continuous and share the properties of that covering the nerve fibers. Small leucine-rich proteoglycans are major proteoglycans of the extracellular matrix and regulate collagen fibrillogenesis, cell signalling pathways and extracellular matrix assembly. Here we used immunohistochemistry to investigate the distribution of class I (biglycan, decorin, asporin, ECM2 and ECMX) and class II (fibromodulin, lumican, prolargin, keratocan and osteoadherin) small leucine-rich proteoglycans in human cutaneous Pacinian corpuscles. The distribution of these compounds was: the inner core express decorin, biglycan, lumican, fibromodulin, osteoadherin; the intermediate layer display immunoreactivity for osteoadherin; the outer core biglycan, decorin, lumican, fibromodulin and osteoadherin; and the capsule contains biglycan, decorin, fibromodulin, and lumican. Asporin, prolargin and keratocan were undetectable. These results complement our knowledge about the distribution of small leucine-rich proteoglycans in human Pacinian corpuscles, and help to understand the composition of the extracellular matrix in these sensory formations.

Periostin, dentin matrix protein 1 and P2rx7 ion channel in human teeth and periodontal ligament.

The periostin is a matricellular protein present in the human periodontal ligament and human dental pulp-derived cells lines, that up-regulates the in vitro expression of some genes involved in the dentin mineralization, such as dentin matrix protein 1 and P2x7-ion channel receptor. Here we investigated the distribution of periostin in human teeth and periodontal ligaments, mapping in parallel the localization of dentin matrix protein 1 and P2x7-ion channel receptor to establish whether or not they are expressed in the same places as periostin. The periodontal ligament and the subodontoblastic layer of the dental pulp displayed strong periostin immunoreactivity, whereas dentin matrix protein 1 was detected in the periodontal ligament co-localized with periostin in the vicinity of the cement. The P2x7 ion channel receptor was regularly absent in both the periodontal ligament and dental tissues, but in some cases, it was observed in the odontoblasts. Present results demonstrate the occurrence of periostin in the healthy adult human tooth without co-localization with proteins involved in tooth mineralization, the expression of which it regulates. These results might serve as a baseline for future studies on pathological conditions.

Vaginal progesterone as maintenance treatment after an episode of preterm labour (PROMISE) study: a multicentre, double-blind, randomised, placebo-controlled trial.

OBJECTIVE: To evaluate whether maintenance treatment with vaginal progesterone after an arrested preterm labour reduces the incidence of preterm delivery. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. SETTING: Twelve tertiary care centres in Spain. POPULATION: A total of 265 women with singleton pregnancy, preterm labour successfully arrested with tocolytic treatment, and cervical length of <25 mm. METHODS: Randomisation was stratified by gestational age (from 24.0 to <31.0 weeks of gestation and from 31.0 to <34.0 weeks of gestation) and centre. Patients were randomly assigned, in a 1 : 1 ratio, to either daily vaginal capsules of 200 mg progesterone or placebo until delivery or 36.6 weeks of gestation, whichever occurred first. MAIN OUTCOME MEASURES: Primary outcome was delivery before 34.0 and 37.0 weeks of gestation. Secondary outcomes were discharge-to-delivery time, readmissions because of preterm labour, emergency service use, and neonatal morbidity and mortality. RESULTS: From June 2008 through June 2012, 1419 women were screened: 472 met the inclusion criteria and 265 were randomised. The final analysis included 258 women: 126 in the progesterone group and 132 in the placebo group. There were no significant differences between the progesterone and placebo groups in terms of delivery at <34 weeks of gestation [9/126 (7.1%) versus 10/132 (7.6%), P = 0.91] or <37 weeks of gestation [36/126 (28.6%) versus 29/132 (22.0%), P = 0.22]. There were no differences observed between groups when considering the two strata of gestational age at inclusion. CONCLUSIONS: A maintenance treatment of 200 mg of daily vaginal progesterone capsules in women discharged home after an episode of arrested preterm labour did not significantly reduce the rate of preterm delivery. TWEETABLE ABSTRACT: Maintenance progesterone in 258 women after arrested PTL showed no benefit.

Osteoprotegerin and zoledronate bone effects during orthodontic tooth movement.

OBJECTIVES: To assess the effects of local delivery of recombinant fusion protein osteoprotegerin (OPG-Fc) and bisphosphonate zoledronate on bone and periodontal ligament in a rat tooth movement model. MATERIALS AND METHODS: Maxillary first molars of 36 male Sprague-Dawley rats were displaced mesially using a calibrated spring connected to an anterior mini-screw. Two different drugs were used: a single dose of Zoledronate (16 µg) and a twice-weekly dose of OPG-Fc (5.0 mg/kg) were injected. Tooth movement was measured on scanned plaster casts. Structural and immunohistochemical analysis of the orthodontic-induced changes in bone included receptor activator of nuclear factor ĸ (RANK), Runx, type 1 collagen, matrix metalloproteinases (MMPs) 2 and 9, tissue inhibitors of metalloproteinases (TIMPs) 1 and 2, and vimentin. RESULTS: Both groups showed a reduction in mesial molar displacement. Animals receiving OPG-Fc demonstrated only 52%, 31%, and 21% of the total mesial molar displacement compared to control rats at 7, 14, and 21 days, respectively (*p < 0.001). For rats receiving zoledronate tooth displacement decreased significantly with 52%, 46% and 30%, respectively (*p < 0.001). At 14 and 21 days, OPG-Fc group showed significantly less molar displacement than the zoledronate group (*p < 0.001). RANK, Runx, vimentin, MMP-9 and tissues-inhibitor metalloproteinase 1 immunoreactivity were reduced in zoledronate treated animals and even more in OPG treated animals. CONCLUSION: Local delivery of OPG-Fc or zoledronate inhibits bone resorption and therefore tooth movement. OPG-Fc was more effective than zoledronate in blocking the action of osteoclasts.

Immunohistochemical localization of periostin in human gingiva.

The periostin is a matricellular protein expressed in collagen-rich tissues including some dental and periodontal tissues where it is regulated by mechanical forces, growth factors and cytokines. Interestingly the expression of this protein has been found modified in different gingival pathologies although the expression of periostin in normal human gingiva was never investigated. Here we used Western blot and double immunofluorescence coupled to laser-confocal microscopy to investigated the occurrence and distribution of periostin in different segments of the human gingival in healthy subjects. By Western blot a protein band with an estimated molecular mass of 94 kDa was observed. Periostin was localized at the epithelial-connective tissue junction, or among the fibers of the periodontal ligament, and never co-localized with cytokeratin or vimentin thus suggesting it is an extracellular protein. These results demonstrate the occurrence of periostin in adult human gingiva; its localization suggests a role in the bidirectional interactions between the connective tissue and the epithelial cells, and therefore in the physiopathological conditions in which these interactions are altered.

Acid-sensing ion channel 2 (ASIC2) is selectively localized in the cilia of the non-sensory olfactory epithelium of adult zebrafish.

Ionic channels play key roles in the sensory cells, such as transducing specific stimuli into electrical signals. The acid-sensing ion channel (ASIC) family is voltage-insensitive, amiloride-sensitive, proton-gated cation channels involved in several sensory functions. ASIC2, in particular, has a dual function as mechano- and chemo-sensor. In this study, we explored the possible role of zebrafish ASIC2 in olfaction. RT-PCR, Western blot, chromogenic in situ hybridization and immunohistochemistry, as well as ultrastructural analysis, were performed on the olfactory rosette of adult zebrafish. ASIC2 mRNA and protein were detected in homogenates of olfactory rosettes. Specific ASIC2 hybridization was observed in the luminal pole of the non-sensory epithelium, especially in the cilia basal bodies, and immunoreactivity for ASIC2 was restricted to the cilia of the non-sensory cells where it was co-localized with the cilia marker tubulin. ASIC2 expression was always absent in the olfactory cells. These findings demonstrate for the first time the expression of ASIC2 in the olfactory epithelium of adult zebrafish and suggest that it is not involved in olfaction. Since the cilium sense and transduce mechanical and chemical stimuli, ASIC2 expression in this location might be related to detection of aquatic environment pH variations or to detection of water movement through the nasal cavity.

Quantitative ultrasound texture analysis of fetal lungs to predict neonatal respiratory morbidity.

OBJECTIVE: To develop and evaluate the performance of a novel method for predicting neonatal respiratory morbidity based on quantitative analysis of the fetal lung by ultrasound. METHODS: More than 13,000 non-clinical images and 900 fetal lung images were used to develop a computerized method based on texture analysis and machine learning algorithms, trained to predict neonatal respiratory morbidity risk on fetal lung ultrasound images. The method, termed 'quantitative ultrasound fetal lung maturity analysis' (quantusFLM™), was then validated blindly in 144 neonates, delivered at 28 + 0 to 39 + 0 weeks' gestation. Lung ultrasound images in DICOM format were obtained within 48 h of delivery and the ability of the software to predict neonatal respiratory morbidity, defined as either respiratory distress syndrome or transient tachypnea of the newborn, was determined. RESULTS: Mean (SD) gestational age at delivery was 36 + 1 (3 + 3) weeks. Among the 144 neonates, there were 29 (20.1%) cases of neonatal respiratory morbidity. Quantitative texture analysis predicted neonatal respiratory morbidity with a sensitivity, specificity, positive predictive value and negative predictive value of 86.2%, 87.0%, 62.5% and 96.2%, respectively. CONCLUSIONS: Quantitative ultrasound fetal lung maturity analysis predicted neonatal respiratory morbidity with an accuracy comparable to that of current tests using amniotic fluid.

The sensory innervation of the human pharynx: searching for mechanoreceptors.

The coordinate neural regulation of the upper airways muscles is basic to control airway size and resistance. The superior constrictor pharyngeal muscle (SCPM) forms the main part of the lateral and posterior walls of the pharynx and typically is devoid of muscle spindles, the main type of proprioceptor. Because proprioception arising from SCPM is potentially important in the physiology of the upper airways, we have investigated if there are mechanical sensory nerve endings substitute for the muscle spindles. Samples of human pharynx were analyzed using immunohistochemistry associated to general axonic and Schwann cells markers (NSE, PGP 9.5, RT-97, and S100P), intrafusal muscle fiber markers, and putative mechanical sense proteins (TRPV4 and ASIC2). Different kinds of sensory corpuscles were observed in the pharynx walls (Pacini-like corpuscles, Ruffini-like corpuscles, spiral-wharves nerve structures, and others) which are supplied by sensory nerves and express putative mechanoproteins. No evidence of muscle spindles was observed. The present results demonstrate the occurrence of numerous and different morphotypes of sensory corpuscles/mechanoreceptors in human pharynx that presumably detect mechanical changes in the upper airways and replace muscle spindles for proprioception. Present findings are of potential interest for the knowledge of pathologies of the upper airways with supposed sensory pathogenesis.

Non-infectious risk factors for different types of cerebral palsy in term-born babies: a population-based, case-control study.

OBJECTIVE: To identify non-infectious antenatal and perinatal risk factors for cerebral palsy (CP) and its subtypes in children born at term. DESIGN: A population-based, case-control study. SETTING: The western healthcare region of Sweden. POPULATION: A population-based series of children with CP born at term during 1983-94 (n=309) was matched with a control group (n=618). METHODS: A total of 62 variables, maternal characteristics, and prepartal, intrapartal and postpartal variables were retrieved from obstetric records. Both univariate and multivariate analyses were performed for spastic and dyskinetic CP, and for the total CP group. MAIN OUTCOME MEASURES: Cerebral palsy (CP) and subtypes. RESULTS: Univariate analysis resulted in 26 significant risk factors for CP. Birthweight (OR 0.54, 95% CI 0.39-0.74), not living with the baby's father (OR 2.58, 95% CI 1.11-5.97), admittance to a neonatal intensive care unit (NICU) (OR 4.43, 95% CI 3.03-6.47), maternal weight at 34 weeks of gestation (OR 1.02, 95% CI 1.00-1.03) and neonatal encephalopathy (OR 69.2, 95% CI 9.36-511.89) were found to be risk factors for CP in the total CP group in our multivariate analysis. Factors during the periods before, during and after delivery were all shown to increase the risk of spastic diplegia and tetraplegia, whereas mostly factors during the period before delivery increased the risk of spastic hemiplegia, and only factors during delivery increased the risk of dyskinetic CP. Admittance to an NICU was a risk factor for all CP subtypes. CONCLUSIONS: The risk factor pattern differed by CP subtype. The presented risk factors may be useful indicators for identifying children at risk of developing CP, and helpful for targeting individuals for early intervention programmes.

Immunohistochemical localization of acid-sensing ion channel 2 (ASIC2) in cutaneous Meissner and Pacinian corpuscles of Macaca fascicularis.

Acid-sensing ion channel 2 (ASIC2) is a member of the degenerin/epithelial sodium channel superfamily, presumably involved mechanosensation. Expression of ASIC2 has been detected in mechanosensory neurons as well as in both axons and Schwann-like cells of cutaneous mechanoreceptors. In these studies we analysed expression of ASIC2 in the cutaneous sensory corpuscles of Macaca fascicularis using immunohistochemistry and laser confocal-scanner microscopy. ASIC2 immunoreactivity was detected in both Meissner and Pacinian corpuscles. It was found to co-localize with neuron-specific enolase and RT-97, but not with S100 protein, demonstrating that ASIC2 expression is restricted to axons supplying mechanoreceptors. These results demonstrate for the first time the presence of the protein ASIC2 in cutaneous rapidly adapting low-threshold mechanoreceptors of monkey, suggesting a role of this ion channel in touch sense.

Mechanosensory neurons, cutaneous mechanoreceptors, and putative mechanoproteins.

The mammalian skin has developed sensory structures (mechanoreceptors) that are responsible for different modalities of mechanosensitivity like touch, vibration, and pressure sensation. These specialized sensory organs are anatomically and functionally connected to a special subset of sensory neurons called mechanosensory neurons, which electrophysiologically correspond with Aß fibers. Although mechanosensory neurons and cutaneous mechanoreceptors are rather well known, the biology of the sense of touch still remains poorly understood. Basically, the process of mechanosensitivity requires the conversion of a mechanical stimulus into an electrical signal through the activation of ion channels that gate in response to mechanical stimuli. These ion channels belong primarily to the family of the degenerin/epithelium sodium channels, especially the subfamily acid-sensing ion channels, and to the family of transient receptor potential channels. This review compiles the current knowledge on the occurrence of putative mechanoproteins in mechanosensory neurons and mechanoreceptors, as well as the involvement of these proteins on the biology of touch. Furthermore, we include a section about what the knock-out mice for mechanoproteins are teaching us. Finally, the possibilities for mechanotransduction in mechanoreceptors, and the common involvement of the ion channels, extracellular membrane, and cytoskeleton, are revisited.

Incidence and clinical implications of early inadvertent septostomy after laser therapy for twin-twin transfusion syndrome.

OBJECTIVE: To evaluate the incidence and clinical outcome of inadvertent septostomy after fetoscopic laser therapy for twin-twin transfusion syndrome (TTTS) and, particularly, to explore its association with the risk of developing pseudoamniotic band syndrome (PABS). METHODS: In a cohort of 414 consecutive monochorionic twin pregnancies with confirmed TTTS treated with laser, the incidence of postoperative septostomy within 1 week of the procedure was recorded prospectively. Rates of preterm delivery, preterm premature rupture of membranes (PPROM), intrauterine fetal demise (IUFD) and PABS were compared among cases with and without septostomy. RESULTS: The mean gestational age at laser therapy was 20.4 (range, 15.3-27.6) weeks. Postoperative septostomy occurred in 30 (7.2%) cases. Pregnancies complicated with septostomy had a significantly higher proportion of preterm delivery before 32 weeks (76.7% vs. 30.2%, P < 0.001), PPROM before 32 weeks (46.7% vs. 19.0%, P < 0.001), IUFD (43.3% vs. 25.8%, P < 0.05) and PABS (13.3% vs. 1.0%, P < 0.001), compared with pregnancies without septostomy. CONCLUSIONS: Inadvertent septostomy occurred in 7% of cases after fetoscopic laser therapy and was associated with a substantially increased risk of adverse perinatal outcome and PABS.

Cervical length and gestational age at admission as predictors of intra-amniotic inflammation in preterm labor with intact membranes.

OBJECTIVES: To evaluate cervical length and gestational age as predictors of intra-amniotic inflammation in patients admitted because of preterm labor and intact membranes. METHODS: Ninety-three pregnant women with preterm labor and intact membranes were included in our study. Cervical length was measured on admission by transvaginal sonography and transabdominal amniocentesis was performed within the first 48 h following admission. Positive amniotic fluid cultures defined intra-amniotic infection. Levels of intra-amniotic interleukin-6 (IL-6) were measured, and a receiver-operating characteristics (ROC) curve was constructed to determine the best cut-off point of IL-6 for predicting intra-amniotic infection. This value was then used as a basis for determining a cut-off of IL-6 for defining intra-amniotic inflammation. Considering inflammatory status, perinatal outcomes were evaluated and compared. Logistic regression was used to investigate associations of different explanatory variables with inflammatory status. A non-invasive approach for detection of intra-amniotic inflammation in women admitted because of preterm labor with intact membranes was evaluated. RESULTS: Intra-amniotic infection and inflammation rates were 14% and 28%, respectively. ROC curve analysis showed that the best cut-off value for IL-6 was 13.4 ng/mL for predicting intra-amniotic infection, which was comparable to the cut-off of 11.3 ng/mL reported previously by other authors (which we used to define inflammation). Regardless of the intra-amniotic microbial status, perinatal outcomes in women who developed intra-amniotic inflammation were worse than in those who did not. Cervical length < 15 mm and gestational age at admission < 28 weeks were independently associated with intra-amniotic inflammation. A strategy considering these two non-invasive parameters (either women admitted < 28 weeks or women admitted between >or= 28 and < 32 weeks with a cervical length < 15 mm) could detect 84.0% of women with intra-amniotic inflammation with a positive predictive value of 48.8%, providing improved diagnostic indices compared to either variable considered alone. CONCLUSIONS: Cervical length and gestational age at admission can be used as a non-invasive method to assess the risk of intra-amniotic inflammation in preterm labor and intact membranes.

Validity of enthesis ultrasound assessment in spondyloarthropathy.

OBJECTIVES: To develop an ultrasound enthesis score and to assess its validity in the diagnostic classification of the spondyloarthropathies (SpAs). METHODS: Twenty-five patients with SpA and 29 healthy controls participated in a blinded, gender-matched, cross-sectional study involving ultrasound assessment. The following entheses were explored bilaterally: proximal plantar fascia, distal Achilles tendon, distal and proximal patellar ligament, distal quadriceps and brachial triceps tendons. The ultrasound score evaluated enthesis thickness, structure, calcifications, erosions, bursae and power Doppler signal. The value of each elemental lesion was calculated using a three-model analysis. Validity was analysed by receiver operating characteristic (ROC) curves. Inter-reader and interexplorer intraclass correlation coefficients (ICCs) were calculated. RESULTS: The logistic regression model overestimated the score of three elemental lesions: calcification (0-3), Doppler (0 or 3) and erosion (0 or 3), while scoring tendon structure, tendon thickness and bursa as 0 or 1. ROC curves established an ultrasound score of >or=18 as the best cut-off point for differentiation between cases and controls. This cut-off point was exceeded by 5/29 controls (17%) and by 21/25 patients with SpA (84%). The sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-) were 83.3%, 82.8%, 4.8% and 0.2%, respectively. The inter-reader and interexplorer ICCs were 0.60 and 0.86, respectively. CONCLUSION: The findings suggest that the ultrasound enthesis score could be a valid tool in the diagnosis of SpA.

Non-typhi Salmonella infection in patients with rheumatic diseases on TNF-alpha antagonist therapy.

OBJECTIVES: The morbidity and mortality of patients with rheumatic diseases has improved considerably following the use of biologic therapies. However, an increase in the frequency of bacterial infections has been observed in patients receiving these drugs. In the present study we aimed to establish the incidence and clinical manifestations of non-typhi Salmonella infection in a large cohort of patients with rheumatic diseases undergoing TNF-alpha antagonist therapy due to severe rheumatic diseases refractory to conventional therapies. METHODS: The rate of non-typhi Salmonella infection found in the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases (BIOBADASER) was compared with that observed in a cohort of rheumatoid arthritis (RA) patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) Study, who were not treated with TNF-alpha antagonists. The rate found in the BIOBADASER registry was also compared with that available in a non-RA historic control cohort reported in a population from Huesca (Northern Spain). RESULTS: Seventeen cases of non-typhi Salmonella infection were observed in the series of patients exposed to anti-TNF-alpha therapies. The incidence rate of non-typhi Salmonella in BIOBADASER was 0.73 per 1000 patient-years (95% confidence interval [CI]: 0.45-1.17). The incidence rate in the EMECAR cohort was 0.44 per 1000 patient-years. The relative risk for non-typhi salmonellosis in RA patients exposed to TNF-alpha inhibitors compared to those not treated with biological therapies was 2.07 (95% CI: 0.27-15.73) (p=0.480) whereas the relative risk of non-typhi Salmonella infections in patients with rheumatic diseases undergoing TNF-alpha antagonist therapy compared with the non-RA Spanish control cohort was 0.63 (95% CI: 0.38-1.04) (p=0.07). Nine of the 17 patients with non-typhi salmonellosis presented a severe systemic infection. CONCLUSION: Incidence of non-typhi Salmonella infection is not increased significantly in rheumatic patients undergoing anti-TNF-alpha therapy when compared with RA patients undergoing conventional DMARD therapy or with the general population. Nevertheless, at least 50% of patients on TNF-alpha have severe complications once they develop non-typhi Salmonella infection. This fact suggests that anti-TNF-alpha therapies may predispose to salmonella dissemination rather than to infection.