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INTRODUCTION AND OBJECTIVE: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. METHODS: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. RESULTS: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to confo

Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the chang

OBJECTIVE: Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed. METHODS: We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring). RESULTS: The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68). CONCLUSION: The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.

DEAD-box proteins are an essential class of enzymes involved in all stages of RNA metabolism. The study of DEAD-box proteins is challenging in a native setting since they are structurally similar, often essential and display dosage sensitivity. Pharmacological inhibition would be an ideal tool to probe the function of these enzymes. In this work, we describe a chemical genetic strategy for the specific inactivation of individual DEAD-box proteins with small molecule inhibitors using covalent complementarity. We identify a residue of low conservation within the P-loop of the nucleotide-binding site of DEAD-box proteins and show that it can be mutated to cysteine without a substantial loss of enzyme function to generate electrophile-sensitive mutants. We then present a series of small molecules that rapidly and specifically bind and inhibit electrophile-sensitive DEAD-box proteins with high selectivity over the wild-type enzyme. Thus, this approach can be used to systematically generate small molecule-sensitive alleles of DEAD-box proteins, allowing for pharmacological inhibition and functional characterization of members of this enzyme family.

DEAD-box proteins are an essential class of enzymes involved in all stages of RNA metabolism. The study of DEAD-box proteins is challenging in a native setting since they are structurally similar, often essential and display dosage sensitivity. Pharmacological inhibition would be an ideal tool to probe the function of these enzymes. In this work, we describe a chemical genetic strategy for the specific inactivation of individual DEAD-box proteins with small molecule inhibitors using covalent complementarity. We identify a residue of low conservation within the P-loop of the nucleotide-binding site of DEAD-box proteins and show that it can be mutated to cysteine without a substantial loss of enzyme function to generate electrophile-sensitive mutants. We then present a series of small molecules that rapidly and specifically bind and inhibit electrophile-sensitive DEAD-box proteins with high selectivity over the wild-type enzyme. Thus, this approach can be used to systematically generate small molecule-sensitive alleles of DEAD-box proteins, allowing for pharmacological inhibition and functional characterization of members of this enzyme family.

Odor representations are initially formed in the olfactory bulb, which contains a topographic glomerular map of odor molecular features. The bulb transmits sensory information directly to piriform cortex, where it is encoded by distributed ensembles of pyramidal cells without spatial order. Intriguingly, piriform cortex pyramidal cells project back to the bulb, but the information contained in this feedback projection is unknown. Here, we use imaging in awake mice to directly monitor activity in the presynaptic boutons of cortical feedback fibers. We show that the cortex provides the bulb with a rich array of information for any individual odor and that cortical feedback is dependent on brain state. In contrast to the stereotyped, spatial arrangement of olfactory bulb glomeruli, cortical inputs tuned to different odors commingle and indiscriminately target individual glomerular channels. Thus, the cortex modulates early odor representations by broadcasting sensory information diffusely onto spatially ordered bulbar circuits.

PURPOSE OF REVIEW: Our current treatment algorithms include only IFN-β and glatiramer as available first-line disease-modifying drugs and natalizumab and fingolimod as second-line therapies. Today, 10 drugs have been approved in Europe and nine in the United States making the choice of therapy more complex. The purpose of the review has been to work out new management algorithms for treatment of relapsing-remitting multiple sclerosis including new oral therapies and therapeutic monoclonal antibodies.RECENT FINDINGS: Recent large placebo-controlled trials in relapsing-remitting multiple sclerosis have shown efficacy of new oral disease-modifying drugs, teriflunomide and dimethyl fumarate, with similar or better efficacy than the injectable disease-modifying drugs, IFN-β and glatiramer acetate. In addition, the new oral drugs seem to have a favorable safety profile. Further, the monoclonal antibody alemtuzumab, which in clinical trials has shown superiority to subcutaneous IFN-β 1a, has been approved in Europe, but not yet in the United States.SUMMARY: In de novo-treated patients, the injectables, IFN-β and glatiramer acetate, will to a great extent be replaced by the new orals, dimethyl fumarate and teriflunomide. However, patients who are stable on an injectable with no or minor side-effects could continue their current therapy. Alemtuzumab should be used as a second-line therapy.

The need for study of behavioral difficulties resulting from exposure to pesticides is based upon reports of behavioral difficulties in aerial applicators following organophosphate poisoning and is underscored by a recent plane crash of a cropduster pilot in which prior exposure to several organophosphate pesticides was implicated. The present study examines effects on performance of pigeons and squirrel monkeys of Phosdrin (mevinphos), a cholinesterase-inhibiting pesticide not previously studied in the laboratory. Variable interval schedules of reinforcement were used with both food and water as rewards. A dose related decrease in response rate was observed with all animals. Decrements in behavior were observed at doses below which external symptoms of Phosdrin poisoning occurred, indicating the need for further investigation of the behavioral actions of pesticides.

Space repellants were tested against mixed field mosquitoes by impregnating wide-mesh bed nets (8-11 threads/cm). The bed nets were taken to the field where human volunteers entered them and collected any mosquitoes that attempted to feed. Eight repellents were tested during a 3-year period. Ent 15510, 2-(2-(2-Butoxyethoxy)ethoxy)ethyl 3-methylcrotonate; Ent 20830, Diisopentyl malate; Ent 22542, N,N-Diethyl-meta-toluamide (deet standard); M- 1960 (standard military clothing repellent); Ent 20297, o-Ethoxy-N,N- diethylbenzamide; Ent 20573, 2-((p-Methoxybenzyl)oxy)N,N-dipropylacetamide; Ent 20364, 1-(o-Ethoxylbenzoyl) piperidine; and all of the repellents were tested at 0.5 gm/gm net weight and 3 were also tested at 0.25 gm/gm net weight., Pub. in Jnl. of Medical Entomology, v9 n2 p149-152, 28 Apr 1972.

Mevinphos (Phosdrin) was found to inhibit the amplitude of hippocampal evoked potentials in unanesthetized squirrel monkeys with chronically indwelling electrodes. The threshold dose was 0.050 mg/kg and the maximal dose studied was 0.200 mg/kg. Doses above 0.200 mg/kg induced hippocampal seizures. Within the dose range of 0.050 mg/kg to 0.200 mg/kg the amplitude and duration of the inhibition were directly proportional to dose. No peripheral signs of poisoning, such as tremor or salivation, were seen at doses of 0.200 mg/kg or under. The discussion emphasizes that mevinphos produces changes in brain function in the absence of the peripheral symptomatology usually taken as indicators of poisoning by aerial applicator personnel. Therefore, it is concluded that exposure to mevinphos may be unexpectedly hazardous since the aerial applicators may be unaware that they have been poisoned. (Author)

Three squirrel monkeys did not respond to visual stimuli for at least one hour following combined administration of mevinphos (Phosdrin) and atropine. Therefore, aerial applicator personnel being treated for mevinphos (Phosdrin) poisoning with atropine may show potentially hazardous dysfunctions of visual perception. Some mechanisms for this effect were discussed. (Author)