Identification of pathological RA endotypes using blood-based biomarkers reflecting tissue metabolism. A retrospective and explorative analysis of two phase III RA studies

There is an increasing demand for accurate endotyping of patients according to their pathogenesis to allow more targeted treatment. We explore a combination of blood-based joint tissue metabolites (neoepitopes) to enable patient clustering through distinct disease profiles. We analysed data from two RA studies (LITHE (N = 574, follow-up 24 and 52 weeks), OSKIRA-1 (N = 131, follow-up 24 weeks)). Two osteoarthritis (OA) studies (SMC01 (N = 447), SMC02 (N = 81)) were included as non-RA comparators. Specific tissue-derived neoepitopes measured at baseline, included: C2M (cartilage degradation); CTX-I and PINP (bone turnover); C1M and C3M (interstitial matrix degradation); CRPM (CRP metabolite) and VICM (macrophage activity). Clustering was performed to identify putative endotypes. We identified five clusters (A-E). Clusters A and B were characterized by generally higher levels of biomarkers than other clusters, except VICM which was significantly higher in cluster B than in cluster A (p<0.001). Biomarker levels in Cluster C were all close to the median, whilst Cluster D was characterised by low levels of all biomarkers. Cluster E also had low levels of most biomarkers, but with significantly higher levels of CTX-I compared to cluster D. There was a significant difference in ΔSHP score observed at 52 weeks (p<0.05). We describe putative RA endotypes based on biomarkers reflecting joint tissue metabolism. These endotypes differ in their underlining pathogenesis, and may in the future have utility for patient treatment selection

Instrumentation, Field Network And Process Automation for the LHC Cryogenic Line Tests

This paper describes the cryogenic control system and associated instrumentation of the test facility for 3 pre-series units of the LHC Cryogenic Distribution Line. For each unit, the process automation is based on a Programmable Logic Con-troller implementing more than 30 closed control loops and handling alarms, in-terlocks and overall process management. More than 160 sensors and actuators are distributed over 150 m on a Profibus DP/PA network. Parameterization, cali-bration and diagnosis are remotely available through the bus. Considering the diversity, amount and geographical distribution of the instru-mentation involved, this is a representative approach to the cryogenic control system for CERN's next accelerator

Instrumentation, Field Network and Process Automation for the Cryogenic System of the LHC Test String

CERN is now setting up String 2, a full-size prototype of a regular cell of the LHC arc. It is composed of two quadrupole, six dipole magnets, and a separate cryogenic distribution line (QRL) for the supply and recovery of the cryogen. An electrical feed box (DFB), with up to 38 High Temperature Superconducting (HTS) leads, powers the magnets. About 700 sensors and actuators are distributed along four Profibus DP and two Profibus PA field buses. The process automation is handled by two controllers, running 126 Closed Control Loops (CCL). This paper describes the cryogenic control system, associated instrumentation, and their commissioning

Neutron Irradiation Tests of Pressure Transducers in Liquid Helium

The superconducting magnets of the future Large Hadron Collider (LHC) at CERN will operate in pressurised superfluid helium (1 bar, 1.9 K). About 500 pressure transducers will be placed in the liquid helium bath for monitoring the filling and the pressure transients after resistive transitions. Their precision must remain better than 100 mbar at pressures below 2 bar and better than 5% for higher pressures (up to 20 bar), with temperatures ranging from 1.8 K to 300 K. All the tested transducers are based on the same principle: the fluid or gas is separated from a sealed reference vacuum by an elastic membrane; its deformation indicates the pressure. The transducers will be exposed to high neutron fluence (2 kGy, 1014 n/cm2 per year) during the 20 years of machine operation. This irradiation may induce changes both on the membranes characteristics (leakage, modification of elasticity) and on gauges which measure their deformations. To investigate these effects and select the transducer to be used in the LHC, a neutron irradiation program is being performed at the CERI cyclotron (CNRS Orléans, France): a cryostat is installed on a beam line, transducers are immersed in liquid helium and irradiated by neutrons (1-20 MeV, 1015 n/cm2). The tested transducers measure the helium bath pressure, the true value of which is given by a warm, unirradiated sensor. Every readout is acquired on-line. This paper presents the results of the first experiments performed during spring, 1999

Human helminth therapy to treat inflammatory disorders - where do we stand?

Parasitic helminths have evolved together with the mammalian immune system over many millennia and as such they have become remarkably efficient modulators in order to promote their own survival. Their ability to alter and/or suppress immune responses could be beneficial to the host by helping control excessive inflammatory responses and animal models and pre-clinical trials have all suggested a beneficial effect of helminth infections on inflammatory bowel conditions, MS, asthma and atopy. Thus, helminth therapy has been suggested as a possible treatment method for autoimmune and other inflammatory disorders in humans

Symptoms after Ingestion of Pig Whipworm Trichuris suis Eggs in a Randomized Placebo-Controlled Double-Blind Clinical Trial

Symptoms after human infection with the helminth Trichuris suis have not previously been described. Exposure to helminths has been suggested as immune therapy against allergy and autoimmune diseases. We randomized adults with allergic rhinitis to ingest a dose of 2500 T. suis eggs or placebo every 21 days for 168 days (total 8 doses) in a double-blind clinical trial. In a previous publication, we reported a lack of efficacy and a high prevalence of adverse gastrointestinal reactions. The aim of the present study was to present a detailed description of the adverse event data and post-hoc analyses of gastrointestinal reactions. Adverse events and severity (mild, moderate, severe) were recorded daily by subjects, classified by organ using MedDRA 10.0, and event rates compared between subjects on T. suis treatment vs. subjects on placebo. T. suis-specific serum IgG antibodies were measured by a fluoroenzymeimmunoassay (Phadia ApS). During 163 days complete follow-up, subjects ingesting T. suis eggs (N = 49) had a three to 19-fold higher rate of events (median duration, 2 days) with gastrointestinal reactions (moderate to severe flatulence, diarrhea, and upper abdominal pain) compared with placebo subjects (N = 47). The highest incidence of affected subjects was seen from the first few days and until day 42 (3rd dose): 63% vs. 29% for placebo; day 163: 76% vs. 49% for placebo. Seroprevalences increased concurrently in the T. suis group: Day 59, 50%; day 90, 91%; day 170, 93%. The combined duration of episodes with onset before day 42 was ≤14 days in 80% of affected subjects. Age, gender, total IgE, and recent intestinal symptoms at baseline did not predict gastrointestinal side effects. In conclusion, during the first 2 months, repeated ingestions of 2500 T. suis eggs caused frequent gastrointestinal reactions lasting up to 14 days, whereas 4 months further treatment mainly provoked a subclinical stimulation

Open questions and misconceptions in the diagnosis and management of anemia in patients with gastrointestinal bleeding

Despite high prevalence of iron deficiency anemia (IDA) in patients with acute or chronic gastrointestinal bleeding (GIB), IDA and iron deficiency (ID) are frequently untreated. Reasons may be misconceptions about the impact and diagnosis of IDA and the efficacy of new treatments. Addressing these misconceptions, this article summarizes current evidence for better understanding and management of GIB-associated IDA. Despite only few controlled studies evaluated the efficacy of iron treatment in patients with GIB, there is consistent evidence suggesting that: (a) IDA should be diligently investigated, (b) effective treatment of ID/IDA improves outcomes such as health-related quality of life and can avoid severe cardiovascular consequences, and (c) intravenous iron should be considered as well-tolerated treatment in this setting. Overall, the misconceptions and practices outlined in this article should be replaced with strategies that are more in line with current guidelines and best practice in GIB and other underlying conditions of ID/IDA.A pesar de la alta prevalencia de anemia por déficit de hierro (ADH) en pacientes con hemorragia digestiva (HD) aguda o crónica, la ADH y el déficit de hierro (DH) son frecuentemente infratratados. Diversos conceptos erróneos sobre el impacto, el diagnóstico y la eficacia de los nuevos tratamientos de la ADH probablemente lo justifican. Para abordar estos errores conceptuales, este artículo resume la evidencia actual para una mejor comprensión y manejo de la ADH. A pesar de que existen pocos estudios controlados que hayan evaluado la eficacia del tratamiento con hierro en pacientes con HD, hay evidencia que sugiere que: (a) la ADH debe ser investigada diligentemente; (b) el tratamiento eficaz del DH/ADH mejora la calidad de vida relacionada con la salud y puede evitar relevantes complicaciones cardiovasculares, y (c) el hierro intravenoso debe ser considerado como un tratamiento bien tolerado en este contexto. En general, los conceptos erróneos y las prácticas inadecuadas descritas en este artículo deben ser reemplazados por estrategias que estén más en línea con las directrices actuales y buenas prácticas clínicas en HD y otras condiciones causantes del DH/ADHinfo:eu-repo/semantics/publishedVersio

Vaccinia Scars Associated with Improved Survival among Adults in Rural Guinea-Bissau

BACKGROUND: In urban Guinea-Bissau, adults with a vaccinia scar had better survival but also a higher prevalence of HIV-2 infection. We therefore investigated the association between vaccinia scar and survival and HIV infection in a rural area of Guinea-Bissau. METHODOLOGY/PRINCIPAL FINDINGS: In connection with a study of HIV in rural Guinea-Bissau, we assessed vaccinia and BCG scars in 193 HIV-1 or HIV-2 infected and 174 uninfected participants. Mortality was assessed after 2½–3 years of follow-up. The analyses were adjusted for age, sex, village, and HIV status. The prevalence of vaccinia scar was associated with age, village, and HIV-2 status but not with sex and schooling. Compared with individuals without any scar, individuals with a vaccinia scar had better survival (mortality rate ratio (MR) = 0.22 (95% CI 0.08–0.61)), the MR being 0.19 (95% CI 0.06–0.57) for women and 0.40 (95% CI 0.04–3.74) for men. Estimates were similar for HIV-2 infected and HIV-1 and HIV-2 uninfected individuals. The HIV-2 prevalence was higher among individuals with a vaccinia scar compared to individuals without a vaccinia scar (RR = 1.57 (95% CI 1.02–2.36)). CONCLUSION: The present study supports the hypothesis that vaccinia vaccination may have a non-specific beneficial effect on adult survival

The genetic basis of multiple sclerosis: a model for MS susceptibility

<p>Abstact</p> <p>Background</p> <p>MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors.</p> <p>Methods</p> <p>A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America.</p> <p>Results</p> <p>For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible. Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state" to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility" is low (i.e., ≤ 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely.</p> <p>Conclusions</p> <p>The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.</p> <p>The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (≤ 5.2%) are even susceptible to getting MS.</p