Infliximab vs. adalimumab in Crohn's disease: results from 327 patients in an Australian and New Zealand observational cohort study.

BACKGROUND: Maintenance anti-tumour necrosis factor-α (anti-TNFα) treatment for Crohn's disease is the standard of care for patients with an inadequate response to corticosteroids and immunomodulators. AIM: To compare the efficacy and safety of infliximab and adalimumab in clinical practice and assess the value of concomitant immunomodulator therapy. METHODS: We performed an observational cohort study in consecutive patients with Crohn's disease qualifying for anti-TNFα treatment in Australia and New Zealand between 2007 and 2011. Demographic and clinical data were prospectively recorded to identify independent factors associated with induction and maintenance of response to infliximab or adalimumab, or to either anti-TNFα therapy. RESULTS: Three hundred and twenty-seven patients (183 infliximab, 144 adalimumab) successfully applied for treatment. Eighty-nine percent responded in all groups and median maintenance of response was similar for the two agents. Concomitant immunomodulator with infliximab, but not adalimumab, demonstrated a significantly longer response overall (P = 0.002), and significantly fewer disease and treatment-related complications (P = 0.017). Corticosteroids at baseline, and/or in the preceding 12 months, were associated with a 9-13 times greater risk of disease flare during maintenance treatment as compared to no corticosteroids (P < 0.0001). Maintenance of response was similar in the anti-TNF naïve and anti-TNF experienced subgroups. CONCLUSIONS: In this large, real-life study, we demonstrate infliximab and adalimumab to have similar response characteristics. However, infliximab requires concomitant immunomodulator to achieve optimal maintenance of response comparable to adalimumab monotherapy. The results of this study will assist clinicians in further optimising patient care in their day-to-day clinical practice.

Methods to induce labour: a systematic review, network meta-analysis and cost-effectiveness analysis.

OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of labour induction methods. METHODS: We conducted a systematic review of randomised trials comparing interventions for third-trimester labour induction (search date: March 2014). Network meta-analysis was possible for six of nine prespecified key outcomes: vaginal delivery within 24 hours (VD24), caesarean section, uterine hyperstimulation, neonatal intensive care unit (NICU) admissions, instrumental delivery and infant Apgar scores. We developed a decision-tree model from a UK NHS perspective and calculated incremental cost-effectiveness ratios, expected costs, utilities and net benefit, and cost-effectiveness acceptability curves. MAIN RESULTS: In all, 611 studies comparing 31 active interventions were included. Intravenous oxytocin with amniotomy and vaginal misoprostol (≥50 µg) were most likely to achieve VD24. Titrated low-dose oral misoprostol achieved the lowest odds of caesarean section, but there was considerable uncertainty in ranking estimates. Vaginal (≥50 µg) and buccal/sublingual misoprostol were most likely to increase uterine hyperstimulation with high uncertainty in ranking estimates. Compared with placebo, extra-amniotic prostaglandin E2 reduced NICU admissions. There were insufficient data to conduct analyses for maternal and neonatal mortality and serious morbidity or maternal satisfaction. Conclusions were robust after exclusion of studies at high risk of bias. Due to poor reporting of VD24, the cost-effectiveness analysis compared a subset of 20 interventions. There was considerable uncertainty in estimates, but buccal/sublingual and titrated (low-dose) misoprostol showed the highest probability of being most cost-effective. CONCLUSIONS: Future trials should be designed and powered to detect a method that is more cost-effective than low-dose titrated oral misoprostol. TWEETABLE ABSTRACT: New study ranks methods to induce labour in pregnant women on effectiveness and cost.

Antibiotics versus control for toxoplasma retinochoroiditis.

BACKGROUND: Acute toxoplasma retinochoroiditis causes transient symptoms of ocular discomfort and may lead to permanent visual loss. Antibiotic treatment primarily aims to reduce the risk of permanent visual loss, recurrent retinochoroiditis, and the severity and duration of acute symptoms. There is uncertainty about the effectiveness of antibiotic treatment. OBJECTIVES: The objective of this review was to compare the effects of antibiotics versus placebo or no treatment for toxoplasma retinochoroiditis. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register - CENTRAL/CCTR, which contains the Cochrane Eyes and Vision Group Specialised Register (Cochrane Library Issue 2, 2001), MEDLINE (1966 to August 2001), EMBASE (1980 to September 2001), Dissertation Abstracts (1861 to June 2001), LILACS (1982 to 1998), Pascal (1984 to March 2000), proceedings of the Association for Research in Vision and Ophthalmology (1980 to 2001), international symposia on uveitis, and reference lists of review articles. Pharmaceutical companies were contacted for unpublished trials. SELECTION CRITERIA: We included randomised controlled trials that compared any systemic antibiotic treatment against placebo or no treatment. Trials that included immunocompromised patients were excluded. DATA COLLECTION AND ANALYSIS: The primary outcomes for this review were visual acuity at least three months after treatment and risk of recurrent retinochoroiditis. Secondary outcomes were improvement in symptoms and signs of intraocular inflammation, size of lesion and adverse events. Effect measures were pooled using a random effects model. MAIN RESULTS: Three trials, which randomised a total of 173 participants, met the inclusion criteria. All trials were methodologically poor. None reported the effect of treatment on visual acuity. Two studies reported results for recurrent retinochoroiditis: one (124 participants) found a significant reduction in participants with chronic recurrent disease who were treated for 14 months: relative risk 0.28 (95% confidence interval 0.10 to 0.78); the other (20 participants) found no evidence of an effect in participants with acute toxoplasma retinochoroiditis (relative risk 1.00, 95% confidence interval 0.07 to 13.87). Two studies reported an improvement in intraocular inflammation in treated compared with untreated participants and one study reported no difference. Two studies found an increased risk of adverse events in treated participants. REVIEWER'S CONCLUSIONS: There is a lack of evidence to support routine antibiotic treatment for acute toxoplasma retinochoroiditis. There is weak evidence to suggest that long-term treatment of patients with chronic recurrent toxoplasma retinochoroiditis may reduce recurrence. Placebo controlled trials of patients with acute and chronic toxoplasma retinochoroiditis affecting any part of the retina are required to determine the effectiveness of antibiotic treatment.

A sensible formulation of the significance test.

The conventional procedure for null hypothesis significance testing has long been the target of appropriate criticism. A more reasonable alternative is proposed, one that not only avoids the unrealistic postulation of a null hypothesis but also, for a given parametric difference and a given error probability, is more likely to report the detection of that difference.

Surface expression of influenza virus neuraminidase, an amino-terminally anchored viral membrane glycoprotein, in polarized epithelial cells.

We have investigated the site of surface expression of the neuraminidase (NA) glycoprotein of influenza A virus, which, in contrast to the hemagglutinin, is bound to membranes by hydrophobic residues near the NH2-terminus. Madin-Darby canine kidney or primary African green monkey kidney cells infected with influenza A/WSN/33 virus and subsequently labeled with monoclonal antibody to the NA and then with a colloidal gold- or ferritin-conjugated second antibody exhibited specific labeling of apical surfaces. Using simian virus 40 late expression vectors, we also studied the surface expression of the complete NA gene (SNC) and a truncated NA gene (SN10) in either primary or a polarized continuous line (MA104) of African green monkey kidney cells. The polypeptides encoded by the cloned NA cDNAs were expressed on the surface of both cell types. Analysis of [3H]mannose-labeled polypeptides from recombinant virus-infected MA104 cells showed that the products of cloned NA cDNA comigrated with glycosylated NA from influenza virus-infected cells. Both the complete and the truncated glycoproteins were found to be preferentially expressed on apical plasma membranes, as detected by immunogold labeling. These results indicate that the NA polypeptide contains structural features capable of directing the transport of the protein to apical cell surfaces and the first 10 amino-terminal residues of the NA polypeptide are not involved in this process.

Chimeric influenza virus hemagglutinin containing either the NH2 terminus or the COOH terminus of G protein of vesicular stomatitis virus is defective in transport to the cell surface.

Chimeric cDNA clones of influenza virus hemagglutinin (HA) were constructed in which the DNA encoding either the NH2 terminus or the COOH terminus of HA was replaced with that of a vesicular stomatitis virus G protein. The chimeric cDNAs (GHA or HAG) were expressed in CV1 cells using the simian virus 40 late replacement promoter. Both chimeric proteins are synthesized, glycosylated, and transported to the rough endoplasmic reticulum. These results show that the NH2-terminal sequences of vesicular stomatitis virus G protein can provide a signal function for translocation and the COOH-terminal sequences can provide the anchor function for the influenza virus HA, when substituted for similar sequences. However, the chimeric glycoproteins were not transported to the Golgi complex or the plasma membrane. The implication of these results in translocation, sorting, and transport processes is discussed.

Achievement test scores in mathematics and science.

Average achievement test scores of the nation's youth in mathematics and science have declined rather steadily since the early 1960's, and this decline is more marked in the higher grades. The average test scores in mathematics and science of high school seniors who have intended to go to college and major in those fields, however, have been quite stable. These findings may have implications for educational policy.

Early syncytium formation by bovine leukemia virus.

Bovine leukemia virus (BLV) from either persistently infected bat cells or fetal lamb kidney cells induced rapid syncytium formation in F81 indicator cells. Distinct syncytia were seen within 2 h after inoculation of cells with highly concentrated (500-fold) cell-free BLV preparations and within 4 to 8 h when unconcentrated cell-free BLV preparations were used. Indicator cell densities of 1 x 10(5) to 2 x 10(5) were optimal for rapid and maximal syncytium formation. Pretreatment of BLV with reference BLV leukemic serum and antiserum prepared against purified BLV significantly inhibited (95%) syncytium formation. Reference bovine viral diarrhea virus serum, foamy-like bovine syncytial virus serum, and control serum had little effect (17% inhibition). Antiserum to BLV gp51 inhibited syncytium formation by greater than 96%, whereas antiserum to BLV p24 reduced syncytium activity to a much lesser extent (38% inhibition). Treatment of BLV with beta-propiolactone (0.005 to 0.05%) had little or no effect upon syncytium-forming activity, whereas UV irradiation (15 ergs/mm(2) per s for 30 min) reduced, but did not completely destroy, the fusion activity. However, both beta-propiolactone and UV irradiation drastically reduced the replication potential of BLV, as demonstrated by the lack of p24 expression in the inoculated cells. Concentrations of cycloheximide, cytosine arabinoside, tunicamycin, and 2-deoxy-D-glucose which effectively blocked cellular macromolecular synthesis did not significantly inhibit syncytium formation. These latter results suggested that de novo protein and DNA synthesis as well as protein glycosylation were not required for early syncytium formation. Thus, these experiments demonstrated that replication of BLV by the indicator cells was not essential for cell fusion.

Anion mass spectrometry of barbiturates.

Recent trends towards increasing abuse of the barbiturates has led to a proposal to legally restrict some of them. The implementation of the resulting legislation might require specific identification of the barbiturates. Such identification is not readily available from electron impact mass spectra and, even when these are supplemented with chemical ionization data, barbiturates differing only in isomeric sidechains are not completely characterized. In this study the anion mass spectra of 30 barbiturates, including all of those commonly available, are presented. The spectra are simple; ions arising from hydrogen atom and sidechain elimination from the initially formed [M]- ion are diagnostic of the barbiturate. For all but two of the barbiturates (butalbital and idobutal) relative peak intensities will discriminate between barbiturates differing only in isomeric sidechains.

The gas chromatography mass spectrometry of the major metabolites of flurazepam.

Mass spectra and gas chromatographic data are presented for flurazepam and its metabolites; monodesethylflurazepam, didesethylflurazepam, hydroxyethylflurazepam, N1-desalkylflurazepam, N1-desalkyl-3-hydroxy-flurazepam, and flurazepam-N1-acetic acid. The on-column thermal degradation of didesethylflurazepam, N1-desalkyl-3-hydroxyflurazepam and flurazepam-N1-acetic acid is reported and discussed. Mass spectrometric and gas chromatographic data are also presented for the benzophenones obtained by acid hydrolysis of flurazepam and its metabolites. The occurrence of flurazepam metabolites in urine from five forensic cases after various treatments has been investigated. A possible new 'metabolite' of flurazepam was detected in two of these cases.