Cost-utility analysis of Interferon Beta-1b in the treatment of different types of Multiple Sclerosis

Background Economic evaluation of treatments in multiple sclerosis (MS) presents a challenge. The disease affects a number of different body functions and leads to severe disability over time, without however a strong effect on mortality. At onset, the majority of patients will have relapsing-remitting disease (RRMS) and will then convert to secondary-progressive disease (SPMS) overtime. However, the course of the disease is unpredictable, and the conversion to SPMS can take place at different times since onset and at different levels of disability for different patients. Relapses appear to occur with the same frequency at all levels of disability, but will diminish over time. The effectiveness of treatments can be measured in different ways such as disease activity, the number and the severity of relapses or the progression of functional disability, regardless of the type of MS. However, improvements in outcome achieved over a short term may have an effect on the disease in the longer term, and effectiveness data from clinical trials must therefore be extrapolated to the longer term, using modelling techniques. This requires good epidemiological data on the natural course of the disease, where disease progression is expressed with the same measures as in the clinical trials. Also to perform economic evaluations, a global outcome measure is required to capture the impact of treatments on the disease and the most frequently used such measure is quality-adjusted life years (QALYs). However, for QALYs to be used in cost-effectiveness analysis of MS, they must be related to a measure of the disease and disease progression. The Expanded Disability Status Scale (EDSS) provides a good measure of the disease and has been widely used in epidemiological studies and clinical trials, in all types of MS. Lastly, detailed economic data that can be related to the different levels of disability (EDSS) are required. Objective We have earlier proposed a basic framework for cost-effectiveness modelling in MS, and the original model has been updated, as new data have become available. The current study proposes a further development of the modelling technique and estimates the cost-effectiveness of treatment with interferon b-1b (IFNB-1b) in a defined patient population with active disease, both RRMS and SPMS, from a societal perspective in Sweden. Methods The framework of the earlier Markov model is used, where states are defined according to EDSS. Transition probabilities for the first years in the model are calculated from clinical trial data, and for the extrapolation from a large epidemiological database on the natural history of MS. In view of the fact that the number of relapses at given levels of disability did not differ between patients with RRMS or SPMS in any of the three datasets used in this analysis, and that conversion from RRMS to SPMS did not occur at well defined levels of disability, we combined data from two large clinical trials in RRMS and SPMS. Patients were selected on whether or not they had active disease at enrolment, defined as an increase in the EDSS by at least 1 point (0.5 points for scores between EDSS 6 and 7) or at least 2 relapses in the preceding 2 years. This allows simulating treatment start at any stage and for any type of the disease and estimating long-term consequences within the same model. The combination of the two types of MS is further supported by the fact that it has been shown in 3 observational studies that costs and quality of life at given EDSS levels are not different for patients with different types of the disease. Transition probabilities between the Markov states are estimated for both the clinical trial and the natural history cohorts using an ordered probit model. Transitions thus depend on several factors, including what state a patient is in, whether or not she/he has a relapse, age, age at onset of the disease, time since onset of the disease, age at treatment start. The base case simulations use mean costs and mean utilities in each state from a large observational study in Sweden. However, the model allows calculating acceptability curves, i.e. the probability with which the cost effectiveness ratio of a treatment scenario is below given levels of willingness-to-pay for a QALY, using the entire distribution of costs and utilities at each EDSS level. Costs and benefits are discounted with 3%. Results The base case assumes treatment with IFNB-1b during 36 months, with no further effect when treatment is stopped, and includes both patients with active RRMS and SPMS. Sensitivity analysis is presented for treatment during 54 months. The annual cost of IFNB-1b treatment was 102 587 SEK plus 1600 SEK for special monitoring, and was adjusted for compliance in the clinical trial. In the base-case treatment adds 13 000 to costs over 10 years, and the cost per QALY gained is 71 400 SEK. When the time horizon is increased to 15-25 years, treatment dominates no treatment (higher utility and lower cost). With treatment during 54 months, the cost per QALY is 353 800 SEK, all costs included. When treatment is started early, the cost-effectiveness ratio is higher, e.g. 643 100 SEK in state 2, as patients in these states progress only very slowly. In the net benefit approach, there is a 80% probability that the treatment initiated in states 3 or 4 (EDSS 4.0-5.5) is cost-effective, if the willingness to pay for a QALY is 400 000 to 600 000 SEK. At that level of willingness to pay, the probability in state 2 is 45%. Conclusions With this new model, which combines active RRMS and SPMS, the effect of early treatment on the long-term outcome can be estimated for the first time using patient-level clinical data for RRMS and SPMS, as well as natural history data. The combination of the two types of MS into one model is supported by the finding that, at given levels of EDSS, there was no difference in the number of annual relapses in the three clinical datasets used, nor in the mean cost and mean utilities in the observational study. The model is more flexible than previous models, as it includes individual patient demographics and the entire distribution of costs and utilities in the different states. It thus represents a valuable tool to estimate the cost-effectiveness of treating different patient groups with IFNB-1b.MS; Cost-effectiveness

Determinants of maternal and fetal exposure and temporal trends of perfluorinated compounds.

In recent years, some perfluorinated compounds (PFCs) have been identified as potentially hazardous substances which are harmful to the environment and human health. According to limited data, PFC levels in humans could be influenced by several determinants. However, the findings are inconsistent. In the present study, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were measured in paired maternal and cord serum samples (N = 237) collected between 1978 and 2001 in Southern Sweden to study the relationship between these and to investigate several potential determinants of maternal and fetal exposure to PFCs. Time trends of PFCs in Swedish women were also evaluated. The study is a part of the Fetal Environment and Neurodevelopment Disorders in Epidemiological Research project. PFOS, PFOA, and PFNA levels (median) were higher in maternal serum (15, 2.1, and 0.24 ng/ml, respectively) than in cord serum (6.5, 1.7, and 0.20 ng/ml, respectively). PFC levels were among the highest in women originating from the Nordic countries and the lowest in women from the Middle East, North Africa, and sub-Saharan Africa. Multiparous women had lower serum PFOA levels (1.7 ng/ml) than primiparous women (2.4 ng/ml). Maternal age, body mass index, cotinine levels, and whether women carried male or female fetuses did not affect serum PFC concentrations. Umbilical cord serum PFC concentrations showed roughly similar patterns as the maternal except for the gestational age where PFC levels increased with advancing gestational age. PFOS levels increased during the study period in native Swedish women. In summary, PFOS levels tend to increase while PFOA and PFNA levels were unchanged between 1978 and 2001 in our study population. Our results demonstrate that maternal country of origin, parity, and gestational age might be associated with PFC exposure

Controversial significance of early S100B levels after cardiac surgery

BACKGROUND: The brain-derived protein S100B has been shown to be a useful marker of brain injury of different etiologies. Cognitive dysfunction after cardiac surgery using cardiopulmonary bypass has been reported to occur in up to 70% of patients. In this study we tried to evaluate S100B as a marker for cognitive dysfunction after coronary bypass surgery with cardiopulmonary bypass in a model where the inflow of S100B from shed mediastinal blood was corrected for. METHODS: 56 patients scheduled for coronary artery bypass grafting underwent prospective neuropsychological testing. The test scores were standardized and an impairment index was constructed. S100B was sampled at the end of surgery, hourly for the first 6 hours, and then 8, 10, 15, 24 and 48 hours after surgery. None of the patients received autotransfusion. RESULTS: In simple linear analysis, no significant relation was found between S100B levels and neuropsychological outcome. In a backwards stepwise regression analysis the three variables, S100B levels at the end of cardiopulmonary bypass, S100B levels 1 hour later and the age of the patients were found to explain part of the neuropsychological deterioration (r = 0.49, p < 0.005). CONCLUSIONS: In this study we found that S100B levels 1 hour after surgery seem to be the most informative. Our attempt to control the increased levels of S100B caused by contamination from the surgical field did not yield different results. We conclude that the clinical value of S100B as a predictive measurement of postoperative cognitive dysfunction after cardiac surgery is limited

APOGEE Data and Spectral Analysis from SDSS Data Release 16: Seven Years of Observations Including First Results from APOGEE-South

The spectral analysis and data products in Data Release 16 (DR16; December 2019) from the high-resolution near-infrared APOGEE-2/SDSS-IV survey are described. Compared to the previous APOGEE data release (DR14; July 2017), APOGEE DR16 includes about 200000 new stellar spectra, of which 100000 are from a new southern APOGEE instrument mounted on the 2.5 m du Pont telescope at Las Campanas Observatory in Chile. DR16 includes all data taken up to August 2018, including data released in previous data releases. All of the data have been re-reduced and re-analyzed using the latest pipelines, resulting in a total of 473307 spectra of 437445 stars. Changes to the analysis methods for this release include, but are not limited to, the use of MARCS model atmospheres for calculation of the entire main grid of synthetic spectra used in the analysis, a new method for filling "holes" in the grids due to unconverged model atmospheres, and a new scheme for continuum normalization. Abundances of the neutron capture element Ce are included for the first time. A new scheme for estimating uncertainties of the derived quantities using stars with multiple observations has been applied, and calibrated values of surface gravities for dwarf stars are now supplied. Compared to DR14, the radial velocities derived for this release more closely match those in the Gaia DR2 data base, and a clear improvement in the spectral analysis of the coolest giants can be seen. The reduced spectra as well as the result of the analysis can be downloaded using links provided in the SDSS DR16 web page

The chemical characterisation of halo substructure in the Milky Way based on APOGEE

Galactic haloes in a $\Lambda$-Cold Dark Matter ($\Lambda$CDM) universe are predicted to host today a swarm of debris resulting from cannibalised dwarf galaxies that have been accreted via the process of hierarchical mass assembly. The chemo-dynamical information recorded in the Galactic stellar populations associated with such systems helps elucidate their nature, placing constraints on the mass assembly history of the Milky Way. Using data from the APOGEE and \textit{Gaia} surveys, we examine APOGEE targets belonging to the following substructures in the stellar halo: Heracles, \textit{Gaia}-Enceladus/Sausage (GES), Sagittarius dSph, the Helmi stream, Sequoia, Thamnos, Aleph, LMS-1, Arjuna, I'itoi, Nyx, Icarus, and Pontus. We examine the distributions of all substructures in chemical space, considering the abundances of elements sampling various nucleosynthetic pathways. Our main findings include: {\it i)} the chemical properties of GES, Heracles, the Helmi stream, Sequoia, Thamnos, LMS-1, Arjuna, and I'itoi match qualitatively those of dwarf satellites of the Milky Way, such as the Sagittarius dSph; {\it ii)} the abundance pattern of the recently discovered inner Galaxy substructure Heracles differs statistically from that of populations formed {\it in situ}. Heracles also differs chemically from all other substructures; {\it iii)} the abundance patterns of Sequoia (selected in various ways), Arjuna, LMS-1, and I'itoi are indistinguishable from that of GES, indicating a possible common origin; {\it iv)} the abundance patterns of the Helmi stream and Thamnos substructures are different from all other halo substructures; {\it v)} the chemical properties of Nyx and Aleph are very similar to those of disc stars, implying that these substructures likely have an \textit{in situ} origin.Comment: Submitted to MNRAS. 39 page

Stellar Characterization and Radius Inflation of Hyades M Dwarf Stars From the APOGEE Survey

We present a spectroscopic analysis of a sample of 48 M dwarf stars ($0.2 M_{\odot}< M < 0.6 M_{\odot}$) from the Hyades open cluster using high-resolution H-band spectra from the SDSS/APOGEE survey. Our methodology adopts spectrum synthesis with LTE MARCS model atmospheres, along with the APOGEE DR17 line list, to determine effective temperatures, surface gravities, metallicities, and projected rotational velocities. The median metallicity obtained for the Hyades M dwarfs is [M/H]= 0.09$\pm$0.03 dex, indicating a small internal uncertainty and good agreement with optical results for Hyades red-giants. Overall, the median radii are larger than predicted by stellar models by 1.6$\pm$2.3\% and 2.4$\pm$2.3\%, relative to a MIST and DARTMOUTH isochrone, respectively. We emphasize, however, that these isochrones are different and the fractional radius inflation for the fully- and partially-convective regimes have distinct behaviors depending on the isochrone. Using a MIST isochrone there is no evidence of radius inflation for the fully convective stars, while for the partially convective M-dwarfs the radii are inflated by 2.7$\pm$2.1\%, which is in agreement with predictions from models that include magnetic fields. For the partially-convective stars, rapid-rotators present on average higher inflation levels than slow-rotators. The comparison with SPOTS isochrone models indicates that the derived M dwarf radii can be explained by accounting for stellar spots in the photosphere of the stars, with 76\% of the studied M dwarfs having up to 20\% spot coverage, and the most inflated stars with $\sim$20 -- 40\% spot coverage.Comment: Accepted for publication by The Astrophysical Journal (ApJ

Decline in Titers of Anti-Idiotypic Antibodies Specific to Autoantibodies to GAD65 (GAD65Ab) Precedes Development of GAD65Ab and Type 1 Diabetes.

The humoral Idiotypic Network consisting of antibodies and their anti-idiotypic antibodies (anti-Id) can be temporarily upset by antigen exposure. In the healthy immune response the original equilibrium is eventually restored through counter-regulatory mechanisms. In certain autoimmune diseases however, autoantibody levels exceed those of their respective anti-Id, indicating a permanent disturbance in the respective humoral Idiotypic Network. We investigated anti-Id directed to a major Type 1 diabetes (T1D)-associated autoantibody (GAD65Ab) in two independent cohorts during progression to disease. Samples taken from participants of the Natural History Study showed significantly lower anti-Id levels in individuals that later progressed to T1D compared to non-progressors (anti-Id antibody index of 0.06 vs. 0.08, respectively, p = 0.02). We also observed a significant inverse correlation between anti-Id levels and age at sampling, but only in progressors (p = 0.014). Finally, anti-Id levels in progressors showed a significant decline during progression as compared to longitudinal anti-Id levels in non-progressors (median rate of change: -0.0004 vs. +0.0004, respectively, p = 0.003), suggesting a loss of anti-Id during progression. Our analysis of the Diabetes Prediction in Skåne cohort showed that early in life (age 2) individuals at risk have anti-Id levels indistinguishable from those in healthy controls, indicating that low anti-Id levels are not an innate characteristic of the immune response in individuals at risk. Notably, anti-Id levels declined significantly in individuals that later developed GAD65Ab suggesting that the decline in anti-Id levels precedes the emergence of GAD65Ab (median rate of change: -0.005) compared to matched controls (median rate of change: +0.001) (p = 0.0016). We conclude that while anti-Id are present early in life, their levels decrease prior to the appearance of GAD65Ab and to the development of T1D

A Tale of Two Disks: Mapping the Milky Way with the Final Data Release of APOGEE

We present new maps of the Milky Way disk showing the distribution of metallicity ([Fe/H]), $\alpha$-element abundances ([Mg/Fe]), and stellar age, using a sample of 66,496 red giant stars from the final data release (DR17) of the Apache Point Observatory Galactic Evolution Experiment (APOGEE) survey. We measure radial and vertical gradients, quantify the distribution functions for age and metallicity, and explore chemical clock relations across the Milky Way for the low-$\alpha$ disk, high-$\alpha$ disk, and total population independently. The low-$\alpha$ disk exhibits a negative radial metallicity gradient of $-0.06 \pm 0.001$ dex kpc$^{-1}$, which flattens with distance from the midplane. The high-$\alpha$ disk shows a flat radial gradient in metallicity and age across nearly all locations of the disk. The age and metallicity distribution functions shift from negatively skewed in the inner Galaxy to positively skewed at large radius. Significant bimodality in the [Mg/Fe]-[Fe/H] plane and in the [Mg/Fe]-age relation persist across the entire disk. The age estimates have typical uncertainties of $\sim0.15$ in $\log$(age) and may be subject to additional systematic errors, which impose limitations on conclusions drawn from this sample. Nevertheless, these results act as critical constraints on galactic evolution models, constraining which physical processes played a dominant role in the formation of the Milky Way disk. We discuss how radial migration predicts many of the observed trends near the solar neighborhood and in the outer disk, but an additional more dramatic evolution history, such as the multi-infall model or a merger event, is needed to explain the chemical and age bimodality elsewhere in the Galaxy.Comment: 41 pages, 32 figures, accepted to Ap