Up to 5-year retention of abatacept in Belgian patients with moderate-to-severe rheumatoid arthritis: a sub-analysis of the international, observational ACTION study.

Favorable efficacy and safety profiles have been demonstrated for abatacept in patients with rheumatoid arthritis (RA) in randomized controlled trials, but these data require validation during long-term follow-ups in routine clinical practice. This study explored long-term safety and retention rates in RA patients treated with intravenous abatacept in the Belgian cohort of the international AbataCepT In rOutiNe clinical practice (ACTION) study (NCT02109666). This non-interventional, observational, longitudinal study included Belgian patients aged ≥ 18 years with moderate-to-severe RA who started intravenous abatacept treatment as first- or second/further-line biologic therapy in routine clinical practice. Between October 2010 and December 2012, 141 patients were enrolled in this cohort, of whom 135 evaluable patients (6 biologic-naïve; 129 previously exposed to ≥ 1 prior biologic disease modifying anti-rheumatic drugs) were eligible for the descriptive analysis; 131/135 were included in the effectiveness analysis. Mean disease duration was 10.5 years (standard deviation 9.7) before abatacept initiation. RA patients presented with high disease activity and comorbidity rate, having failed multiple previous treatment options. In this cohort, the 5-year abatacept retention rate was 34% (95% confidence interval, 23-45%) per protocol, and 51% (95% confidence interval, 40-61%) when temporary discontinuations of abatacept > 84 days (n = 24) were not considered as treatment discontinuations. After 5 years of abatacept treatment, clinical outcomes were favorable [good/moderate European League Against Rheumatism (EULAR) responses in 91.7% patients]. No new safety signals were detected for abatacept in routine clinical practice. In this difficult-to-treat Belgian RA population, high retention rates, good clinical outcomes and favorable safety profile were observed with abatacept.

Novel computed tomography-based tools reliably quantify plant reproductive investment.

The flower is a bisexual reproductive unit where both genders compete for resources. Counting pollen and ovules in flowers is essential to understand how much is invested in each gender. Classical methods to count very numerous pollen grains and ovules are inefficient when pollen grains are tightly aggregated, and when fertilization rates of ovules are unknown. In this study we have therefore developed novel counting techniques based on computed tomography. In order to demonstrate the potential of our methods in very difficult cases, we counted pollen and ovules across inflorescences of deceptive and rewarding species of European orchids, which possess both very large numbers of pollen grains (tightly aggregated) and ovules. Pollen counts did not significantly vary across inflorescences and pollination strategies, whereas deceptive flowers had significantly more ovules than rewarding flowers. The within-inflorescence variance of pollen-to-ovule ratios in rewarding flowers was four times higher than in deceptive flowers, possibly demonstrating differences in the constraints acting on both pollination strategies. We demonstrate the inaccuracies and limitations of previously established methods, and the broad applicability of our new techniques: they allow measurement of reproductive investment without restriction on object number or aggregation, and without specimen destruction.

Quasifree (p, 2p) Reactions on Oxygen Isotopes: Observation of Isospin Independence of the Reduced Single-Particle Strength.

Quasifree one-proton knockout reactions have been employed in inverse kinematics for a systematic study of the structure of stable and exotic oxygen isotopes at the R^{3}B/LAND setup with incident beam energies in the range of 300-450 MeV/u. The oxygen isotopic chain offers a large variation of separation energies that allows for a quantitative understanding of single-particle strength with changing isospin asymmetry. Quasifree knockout reactions provide a complementary approach to intermediate-energy one-nucleon removal reactions. Inclusive cross sections for quasifree knockout reactions of the type ^{A}O(p,2p)^{A-1}N have been determined and compared to calculations based on the eikonal reaction theory. The reduction factors for the single-particle strength with respect to the independent-particle model were obtained and compared to state-of-the-art ab initio predictions. The results do not show any significant dependence on proton-neutron asymmetry.

Strong Neutron Pairing in core+4n Nuclei.

The emission of neutron pairs from the neutron-rich N=12 isotones ^{18}C and ^{20}O has been studied by high-energy nucleon knockout from ^{19}N and ^{21}O secondary beams, populating unbound states of the two isotones up to 15 MeV above their two-neutron emission thresholds. The analysis of triple fragment-n-n correlations shows that the decay ^{19}N(-1p)^{18}C^{*}→^{16}C+n+n is clearly dominated by direct pair emission. The two-neutron correlation strength, the largest ever observed, suggests the predominance of a ^{14}C core surrounded by four valence neutrons arranged in strongly correlated pairs. On the other hand, a significant competition of a sequential branch is found in the decay ^{21}O(-1n)^{20}O^{*}→^{18}O+n+n, attributed to its formation through the knockout of a deeply bound neutron that breaks the ^{16}O core and reduces the number of pairs.

First observation of the unbound nucleus 15Ne.

We report on the first observation of the unbound proton-rich nucleus 15Ne. Its ground state and first excited state were populated in two-neutron knockout reactions from a beam of 500 MeV/u 17Ne. The 15Ne ground state is found to be unbound by 2.522(66) MeV. The decay proceeds directly to 13O with simultaneous two-proton emission. No evidence for sequential decay via the energetically allowed 2- and 1- states in 14F is observed. The 15Ne ground state is shown to have a strong configuration with two protons in the (sd) shell around 13O with a 63(5)% (1s1/2)2 component.

Measurement of the dipole polarizability of the unstable neutron-rich nucleus 68Ni.

The E1 strength distribution in 68Ni has been investigated using Coulomb excitation in inverse kinematics at the R3B-LAND setup and by measuring the invariant mass in the one- and two-neutron decay channels. The giant dipole resonance and a low-lying peak (pygmy dipole resonance) have been observed at 17.1(2) and 9.55(17) MeV, respectively. The measured dipole polarizability is compared to relativistic random phase approximation calculations yielding a neutron-skin thickness of 0.17(2) fm. A method and analysis applicable to neutron-rich nuclei has been developed, allowing for a precise determination of neutron skins in nuclei as a function of neutron excess.

Over-production of exopolysaccharide by Lacticaseibacillus rhamnosus CNCM I-3690 strain cutbacks its beneficial effect on the host.

Most lactobacilli produce extracellular polysaccharides that are considered to contribute to the probiotic effect of many strains. Lacticaseibacillus rhamnosus CNCM I-3690 is an anti-inflammatory strain able to counterbalance gut barrier dysfunction. In this study ten spontaneous variants of CNCM I-3690 with different EPS-production were generated and characterized by their ropy phenotype, the quantification of the secreted EPS and genetic analysis. Amongst them, two were further analysed in vitro and in vivo: an EPS over-producer (7292) and a low-producer derivative of 7292 (7358, with similar EPS levels than the wild type (WT) strain). Our results showed that 7292 does not have anti-inflammatory profile in vitro, and lost the capacity to adhere to the colonic epithelial cells as well as the protective effect on the permeability. Finally, 7292 lost the protective effects of the WT strain in a murine model of gut dysfunction. Notably, strain 7292 was unable to stimulate goblet cell mucus production and colonic IL-10 production, all key features for the beneficial effect of the WT strain. Furthermore, transcriptome analysis of colonic samples from 7292-treated mice showed a down-regulation of anti-inflammatory genes. Altogether, our results point out that the increase of EPS production in CNCM I-3690 impairs its protective effects and highlight the importance of the correct EPS synthesis for the beneficial effects of this strain.

Direct mass measurements of 19B, 22C, 29F, 31Ne, 34Na and other light exotic nuclei.

We report on direct time-of-flight based mass measurements of 16 light neutron-rich nuclei. These include the first determination of the masses of the Borromean drip-line nuclei (19)B, (22)C, and (29)F as well as that of (34)Na. In addition, the most precise determinations to date for (23)N and (31)Ne are reported. Coupled with recent interaction cross-section measurements, the present results support the occurrence of a two-neutron halo in (22)C, with a dominant ν2s(1/2)(2) configuration, and a single-neutron halo in (31)Ne with the valence neutron occupying predominantly the 2p(3/2) orbital. Despite a very low two-neutron separation energy the development of a halo in (19)B is hindered by the 1d(5/2)(2) character of the valence neutrons.

Migration of nuclear shell gaps studied in the d(24Ne,pγ)25Ne reaction.

The transfer of neutrons onto 24Ne has been measured using a reaccelerated radioactive beam of 24Ne to study the (d,p) reaction in inverse kinematics. The unusual raising of the first 3/2+ level in 25Ne and its significance in terms of the migration of the neutron magic number from N=20 to N=16 is put on a firm footing by confirmation of this state's identity. The raised 3/2+ level is observed simultaneously with the intruder negative parity 7/2- and 3/2- levels, providing evidence for the reduction in the N=20 gap. The coincident gamma-ray decays allowed the assignment of spins as well as the transferred orbital angular momentum. The excitation energy of the 3/2+ state shows that the established USD shell model breaks down well within the sd model space and requires a revised treatment of the proton-neutron monopole interaction.

Relative efficiency of chlamydia screening in non-clinical settings in two California counties.

We examined the relative efficiency of non-clinical sites to screen for chlamydia in youth and young adults. Chlamydia screening targeting youth (under 30 years of age) was performed at non-clinical sites in high-morbidity neighbourhoods of two California counties. Venues were subdivided into community outreach, schools, parenting centres and drug treatment/correctional facilities. Relative efficiency was estimated with multivariate Poisson regression using incidence of chlamydia per person-hours labour adjusting for strategy and county. Among the 1514 youths screened, the overall prevalence of chlamydia was 5.5%. By venue, the highest prevalence was in drug treatment/correction facilities at 11.1% followed by parenting centres at 6.3%, community outreach at 4.9% and schools at 4.6%. Drug treatment/correctional facilities were the most labour time efficient at 9.9 person-hours per chlamydia case. Schools and parenting centres had the lowest cost per screen at 0.9 person-hours per screen. Adjusted relative labour time efficiency (chlamydia cases per paid person-hour) was significantly higher in schools, 2.0 (95% confidence interval [CI] 1.0-4.2), parenting centres, 3.2 (95% CI 1.6-6.6) and drug treatment/correctional facilities, 2.9 (95% CI 1.0-7.8), compared with community outreach. In conclusion, parenting centres and drug treatment centres and correctional facilities are the most efficient venues for chlamydia screening.

[Anti-RH1 (anti-D) alloimmunization after transfusion of platelet concentrates from RH :1 donors]. / Allo-immunisation anti-RH1 (anti-D) après transfusion de concentrés plaquettaires issus de donneurs RH :1.

Anti-erythrocyte alloimmunization may occur following the transfusion of platelet concentrates, in response to the presence of residual erythrocytes. Immunization against RH1 (D) antigen is the most frequent, but transfusion of RH1 compatible platelet concentrates is not always possible because of supply constraints. We report here three cases of anti-RH1 (anti-D) alloimmunization in RH :-1 patients after transfusion of platelet concentrates from RH :1 donors. Criteria for selection of platelet concentrates are numerous and difficult to achieve in practice. Respect of RH1 compatibility is not obligatory, but in case of transfusion of RH1 incompatible platelet concentrates, anti-RH1 immunoprophylaxis must be made for RH :-1 women of child-bearing age and without profound immunosuppression, as recommended by Afssaps (Agence française de sécurité sanitaire des produits de santé). These data point out the need to perform post-transfusional screening test for irregular erythrocyte antibodies as part of the transfusion of platelet concentrates.

Malnutrition with hypoaminoacidemia in a 22-year-old pregnant patient masking a likely ornithine transcarbamylase deficiency.

BACKGROUND: Symptoms and clinical presentations of OTC deficiency vary widely according to the remaining activity of the enzyme. Three factors determine the residual enzyme activity. First, as the OTC gene is carried on the X chromosome, a complete inactivation of this enzyme in a newborn boy results an acute ammonia intoxication. Second, the female mosaicism due to lyonization (differential randomized X-inactivation) leads to differential OTC expression in hepatocytes. Third, the degree of severity depends on the mutation and the level of remaining activity it leaves to the protein. Published cases of OTC deficiency during pregnancy are scant. Most often, diagnosis of the metabolic disease is made before pregnancy or during the post-partum period. METHODS: We report the case of a 22-year-old woman's successful pregnancy with a moderate form of ornithine transcarbamylase (OTC) deficiency, unsuspected before pregnancy, biochemically consistent with plasma aminoacidogram and orotic acid analysis, and initially masked by malnutrition. RESULTS - CONCLUSION: Although maternal ammonia was subnormal and the neonate was safe, an OTC deficiency was revealed by stress factors such as the pregnancy itself and infection, and associated with uncontrollable maternal vomiting and psychiatric syndrome. However, this metabolic disease, revealed by aminoacidogram and urine orotic acid analysis, fortunately did not prevent a successful pregnancy. Even if infrequent, this situation deserves to be highlighted.

[Evaluation of continuous education in transfusion for professionals in hospitals and clinics]. / Evaluation d'un enseignement en transfusion sanguine proposé aux professionnels des établissements de santé.

Professional health workers need continuous update of knowledge in blood transfusion practice. To fulfill this expectation, the "Etablissement français du sang (E.F.S) Auvergne-Loire", in cooperation with the Department of Regional Affairs in Health Services in the Auvergne region, has set up a proximity-based and a dedicated continuous education course, for more than three years. The content of this update course was based upon regulatory recommendations. The course is one day long; an evaluation of the course by the teachers as well as an evaluation of the teachers' level after the course is carried out. Each course attendant is given a CD-ROM which comprises all of the presentations of the day, along with relevant law texts. We now report on our experience in teaching 127 individual professionals in eight sessions: 95% gave full appreciation. This experience reached - up to now - 53% of the public and private hospitals with transfusion services in the Auvergne region and the Loire district and 90% of structures having remote blood banks. This experience can easily be extended to other regional E.F.S. settings.

[Fetal scalp pH during labor: Which threshold for intervention?] / pH au scalp pendant le travail : quel seuil décisionnel pour intervenir ?

OBJECTIVE: In case of abnormal fetal heart rate, there is no consensus on the decision threshold pH scalp leading to a rapid birth. The objective of this study was to compare neonatal issues and cesarean rate in two maternity using different decision thresholds of scalp pH. MATERIAL AND METHODS: A comparative retrospective study conducted in two level III maternity units between January 2013 and May 2014, one maternity unit used a decision threshold of 7.20 (maternity unit 7,20), and the other one a threshold of 7.25 (maternity unit 7,25). An adverse neonatal outcome was defined by a composite endpoint of neonatal morbidity. The risk of cesarean was assessed using a multivariate analysis. RESULTS: One hundred and four patients were included in the maternity unit 7,20 and 163 patients in the maternity 7,25. Adverse neonatal outcome was similar in both maternities (25% vs. 30,1%; P=0.4). The average pH at birth was similar in both maternities, as well as the Apgar score at 5minutes and neonatal transfer rates. However, BE<-12 was more frequent in maternity using 7,20 scalp pH threshold (7% vs. 0%; P<0.01). The cesarean rate was higher in maternity 7,25 (adjusted OR=2.23 95% CI [1.17-4.25]). CONCLUSION: It seems that a decisional threshold fixed to 7,20 could be used reasonably. It could allow to reduce cesarean rate. Other studies are, however, needed to confirm that such threshold of 7,20 does not increase the risk of severe acidosis.

Validation of a novel Multi-Gas sensor for volcanic HCl alongside H2S and SO2 at Mt. Etna.

Volcanic gas emission measurements inform predictions of hazard and atmospheric impacts. For these measurements, Multi-Gas sensors provide low-cost in situ monitoring of gas composition but to date have lacked the ability to detect halogens. Here, two Multi-Gas instruments characterized passive outgassing emissions from Mt. Etna's (Italy) three summit craters, Voragine (VOR), North-east Crater (NEC) and Bocca Nuova (BN) on 2 October 2013. Signal processing (Sensor Response Model, SRM) approaches are used to analyse H2S/SO2 and HCl/SO2 ratios. A new ability to monitor volcanic HCl using miniature electrochemical sensors is here demonstrated. A "direct-exposure" Multi-Gas instrument contained SO2, H2S and HCl sensors, whose sensitivities, cross-sensitivities and response times were characterized by laboratory calibration. SRM analysis of the field data yields H2S/SO2 and HCl/SO2 molar ratios, finding H2S/SO2 = 0.02 (0.01-0.03), with distinct HCl/SO2 for the VOR, NEC and BN crater emissions of 0.41 (0.38-0.43), 0.58 (0.54-0.60) and 0.20 (0.17-0.33). A second Multi-Gas instrument provided CO2/SO2 and H2O/SO2 and enabled cross-comparison of SO2. The Multi-Gas-measured SO2-HCl-H2S-CO2-H2O compositions provide insights into volcanic outgassing. H2S/SO2 ratios indicate gas equilibration at slightly below magmatic temperatures, assuming that the magmatic redox state is preserved. Low SO2/HCl alongside low CO2/SO2 indicates a partially outgassed magma source. We highlight the potential for low-cost HCl sensing of H2S-poor HCl-rich volcanic emissions elsewhere. Further tests are needed for H2S-rich plumes and for long-term monitoring. Our study brings two new advances to volcano hazard monitoring: real-time in situ measurement of HCl and improved Multi-Gas SRM measurements of gas ratios.

[Per partum acidosis: Interest and feasibility of cerebral Doppler during labor]. / Intérêt et faisabilité du Doppler cérébral en cours de travail pour prédire une acidose néonatale.

OBJECTIVES: To evaluate feasibility and interest of fetal cerebral Doppler during labor and the link with fetal pH to predict perinatal fetal asphyxia. METHODS: Our prospective study in a university perinatal center, included patients during labor. There were no risk factors during pregnancy and patients were included after 37 weeks of pregnancy. For each patient an ultrasound with cerebral Doppler was done concomitant to a fetal scalp blood sample. We collected maternal and fetal characteristics as well as cervix dilatation, fetal heart rate analysis and fetal presentation. RESULTS: Among 49 patients included over a period of 4 months, cerebral Doppler failed in 7 cases (11%). Majority of failure occurred at 10cm of dilatation (P=0.007, OR=14.1 [1.483; 709.1275]). Others factors like: maternal age, body mass index, parity, history of C-Section were not associated with higher rate of failure. We did not found either significant correlation between cerebral fetal Doppler and pH on fetal scalp blood sample (r=0.15) nor pH at cord blood sample (r=0.13). No threshold of cerebral Doppler is significant for fetal asphyxia prediction. CONCLUSION: Fetal cerebral Doppler is feasible during labor with a low rate of failure but not a good exam to predict fetal acidosis and asphyxia.

[Analysis of cell-free DNA in maternal blood for detection of fetal trisomy 21 in high-risk population: Couples acceptance and grounds for refusal]. / Étude de l'ADN fœtal dans le sang maternel pour la détection de la trisomie 21 en population à risque accru : adhésion des couples et motifs de refus.

OBJECTIVES: To assess the determinants associated with the use of analysis of cell-free DNA in maternal blood for detection of trisomy 21 in high-risk women. MATERIALS AND METHODS: Prospective study conducted in a single center between July 15, 2014 and December 15, 2014 on 99 consecutive women with increased risk of trisomy 21 above 1/250. RESULTS: Analysis of cell-free DNA in maternal blood for detection of fetal trisomy 21 was proposed to 95 women out of 99, among them, 43 women (45.3%) required the test. Among these 43 women, 17 (38.6%) had a higher socio-economic status versus 10 (19.2%) among the women who did not request the test (P=0.03). The most common reason given by the 52 women who did not request the analysis of cell-free DNA was the cost, for 30 of them (57.7%), then because the test was not providing certainty for the diagnostic of trisomy 21 for 23 women (44.2%). CONCLUSION: Analysis of cell-free DNA on maternal blood for detection of trisomy 21 does not seem accepted by the majority of women. The cost is probably the main reason for not using this test, but it seems that the lack of diagnostic certainty is also an obstacle for some women.

The membrane channel-forming colicin A: synthesis, secretion, structure, action and immunity.

The study of colicin release from producing cells has revealed a novel mechanism of secretion. Instead of a built-in 'tag', such as a signal peptide containing information for secretion, the mechanism employs coordinate expression of a small protein which causes an increase in the envelope permeability, resulting in the release of the colicin as well as other proteins. On the other hand, the mechanism of entry of colicins into sensitive cells involves the same three stages of protein translocation that have been demonstrated for various cellular organelles. They first interact with receptors located at the surface of the outer membrane and are then transferred across the cell envelope in a process that requires energy and depends upon accessory proteins (TolA, TolB, TolC, TolQ, TolR) which might play a role similar to that of the secretory apparatus of eukaryotic and prokaryotic cells. At this point, the type of colicin described in this review interacts specifically with the inner membrane to form an ion channel. The pore-forming colicins are isolated as soluble proteins and yet insert spontaneously into lipid bilayers. The three-dimensional structures of some of these colicins should soon become available and site-directed mutagenesis studies have now provided a large number of modified polypeptides. Their use in model systems, particularly those in which the role of transmembrane potential can be tested for polypeptide insertion and ionic channel gating, constitutes a powerful handle with which to improve our understanding of the dynamics of protein insertion into and across membranes and the molecular basis of membrane excitability. In addition, their immunity proteins, which exist only in one state (membrane-inserted) will also contribute to such an understanding.

Structure of DNA-RecA complexes studied by residue differential linear dichroism and fluorescence spectroscopy for a genetically engineered RecA protein.

The structure of complexes of RecA with double-stranded and single-stranded DNA was studied by linear dichroism spectroscopy, fluorescence quenching and fluorescence anisotropy measurements. One of the two tryptophan residues (Trp291) of RecA was replaced by genetic engineering for an ultraviolet light-transparent threonine. This modified RecA protein shows, within experimental errors, the same DNA-binding kinetics and stoichiometry as the wild-type protein and no significant variation with respect to in vivo repair function was observed between cells with the two protein forms. By comparing the dichroic and fluorescence properties of the wild-type versus the modified protein, when bound to DNA, information about orientation and environment of the Trp291 chromophore in the complex could be obtained. The indole chromophore of Trp291Z was found to be oriented with its pseudo-long axis tilted 61 degrees and the aromatic plane is tilted 27 degrees relative to the fibre axis. Trp291 shows low mobility within the protein and therefore the deduced orientation may be used as a "handle" on the protein at the construction of three-dimensional models of RecA-DNA complexes. Comparison with the orientation for this residue in the crystal structure of the RecA homopolymer fibre indicates no measurable reorientation of the C-terminal subdomain of RecA upon DNA binding. Whereas the accuracy of the orientation determination of tryptophan, in absolute terms, is rather poor, changes of its orientation can be detected with high precision. Thus, similar Trp291 orientations are obtained in the complexes with single-stranded and double-stranded DNA, indicating similar structures of the protein fibres. The fluorescence quenching results indicate that the protein region of Trp291 is not involved in the binding of DNA.

Complete nucleotide sequence of the structural gene for colicin A, a gene translated at non-uniform rate.

The complete nucleotide sequence of the structural gene for colicin A has been established. This sequence consists of 1776 base-pairs. According to the predicted amino acid sequence, the colicin A polypeptide chain comprises 592 amino acids and has a molecular weight of 62,989. The amino-terminal part is rich in proline and glycine and accordingly secondary structure prediction indicates that this region (1 to 185) is beta-structured. The rest of the molecule (residues 186 to 592) is very rich in alpha-helix. An uncharged amino acid sequence of 48 residues is located in the C-terminal part of the molecule, which is involved in the membrane depolarization caused by colicin A. A similar region has been found in colicin E1, which has the same mode of action as colicin A. Three peptides of these bacteriocins were found to be homologous, but a comparison of the bacteriocin genes did not reveal any significant homology out of the corresponding regions. The codon usage of both genes, however, exhibits some similarity and is quite different from that of genes coding for highly or weakly expressed proteins of Escherichia coli.