Lääketeollisuuden pitkän aikavälin logistiikkatarpeet

In this master's thesis was analyzed, how a large pharmaceutical company can improve its forecasting of the long-term need for warehouse capacity. To support its strategic planning, the company wanted to develop a forecast tool and process, with which the company's global need for warehouse capacity could be forecast up to the next ten years. Creating a forecast tool and process was the goal of the mother project of this thesis. In this thesis was analyzed and evaluated, what requirements the long-term forecasting of warehouse capacity needs set for forecast tools and their input data. Furthermore, this thesis evaluated, what feasible forecast tools exist and whether they can be applied at the company. The first phase of the master's thesis showed that academic research provides few tools for forecasting long-term warehouse capacity needs. The provided models and tools are often short-term optimization tools that require highly detailed input data and therefore cannot be used for high-level global planning. An interview series conducted with selected industries showed that the long-term forecasting of warehouse capacity needs requires not only suitable tools, but also good data management and seamless system integration. In addition, supply chains have to be more flexible in the future, which requires collaborative forecasting of warehouse capacity needs with customers and suppliers. This master's thesis also evaluated the feasibility of three different modeling concepts for one of the client company's sites. The initial results show that currently the implementation of any of the concepts is difficult, due to problems in data management and systems integration. However, one of the concepts may provide a forecast tool to be used companywide in the futureTässä työssä tutkittiin, millä tavalla suuri lääkealan yritys voi parantaa ennusteitaan pitkän aikavälin varastotilan tarpeelle. Strategisen suunnittelun tukemiseksi yritys halusi kehittää ennustetyökalun, jolla yrityksen globaali varastokapasiteetin tarve voidaan ennustaa jopa kymmenen vuoden päähän. Ennustetyökalun ja -prosessin luominen olivat tämän diplomityön emoprojektin päämäärä. Tämä diplomityö tutki ja arvioi, mitä vaatimuksia pitkän aikavälin varastokapasiteetin ennustaminen asettaa ennustetyökaluille ja niiden tarvitsemille lähtötiedoille. Lisäksi tässä diplomityössä tutkittiin, millaisia ennustyökaluja on olemassa ja voidaanko niitä soveltaa toimeksiantajan tarpeisiin. Diplomityön ensivaiheessa tehty kirjallisuusanalyysi paljasti, että akateeminen tutkimus ei juuri tarjoa työkaluja pitkän aikavälin varastotarpeen suunnitteluun. Tarjotut mallit ja työkalut ovat usein lyhyemmän aikavälin optimointityökaluja, jotka vaativat erittäin yksityiskohtaisia lähtötietoja eivätkä näin sovellu globaaliin ylätason suunnitteluun. Muilla teollisuudenaloilla toimivissa yrityksissä tehtyjen haastattelujen perusteella varastokapasiteetin pitkän aikavälin ennustaminen vaatii sopivan ennustetyökalun lisäksi hyvää tiedonhallintaa ja eri työkalujen ja tietojärjestelmien saumatonta integrointia. Lisäksi toimitusketjujen täytyy olla tulevaisuudessa joustavampia, jolloin varastokapasiteetin suunnittelussa täytyy tehdä tiivistä yhteistyötä asiakkaiden ja toimittajien kanssa. Diplomityössä arvioitiin kolmen eri työkalukonseptin soveltuvuutta yhdellä toimeksiantoyrityksen toimipaikalla. Alustavien tulosten mukaan jokaisen työkalun käyttöönotto on nykyisellään vaikeaa, koska tiedonhallinta ja tietojärjestelmien integrointi eivät ole riittävän korkealla tasolla. Yksi kolmesta konseptista on alustavan arvion mukaan kuitenkin myöhemmin toteutettavissa, ja sen pohjalta on mahdollista luoda ennustetyökalu koko yrityksen käyttöön

Quantifying the non-linear dependence of energetic electron fluxes in the Earth's radiation belts with radial diffusion drivers

In this study, we use mutual information to characterise statistical dependencies of seed and relativistic electron fluxes in the Earth's radiation belts on ultra-low-frequency (ULF) wave power measured on the ground and at geostationary orbit. The benefit of mutual information, in comparison to measures such as the Pearson correlation, lies in the capacity to distinguish non-linear dependencies from linear ones. After reviewing the property of mutual information and its relationship with the Pearson correlation for Gaussian bivariates, we present a methodology to quantify and distinguish linear and non-linear statistical dependencies that can be generalised to a wide range of solar wind drivers and magnetospheric responses. We present an application of the methodology by revisiting the case events studied by Rostoker et al. (1998). Our results corroborate the conclusions of Rostoker et al. (1998) that ULF wave power and relativistic electron fluxes are statistically dependent upon one another. We also estimate that the Pearson correlation is missing between 20 % and 30 % of the statistical dependency between ULF wave power and relativistic electron fluxes. Thus, the Pearson correlation underestimates the impact of ULF waves on energetic electron fluxes. However, we find that observed enhancements in relativistic electron fluxes correlate modestly, both linearly and non-linearly, with the ULF power spectrum when compared with values found in previous studies (Simms et al., 2014) and with correlational values found between seed electrons and ULF wave power for the same case events. Our results are indicative of the importance of incorporating data analysis tools that can quantify linear and non-linear interdependencies of various solar wind drivers.In this study, we use mutual information to characterise statistical dependencies of seed and relativistic electron fluxes in the Earth's radiation belts on ultra-low-frequency (ULF) wave power measured on the ground and at geostationary orbit. The benefit of mutual information, in comparison to measures such as the Pearson correlation, lies in the capacity to distinguish non-linear dependencies from linear ones. After reviewing the property of mutual information and its relationship with the Pearson correlation for Gaussian bivariates, we present a methodology to quantify and distinguish linear and non-linear statistical dependencies that can be generalised to a wide range of solar wind drivers and magnetospheric responses. We present an application of the methodology by revisiting the case events studied by Rostoker et al. (1998). Our results corroborate the conclusions of Rostoker et al. (1998) that ULF wave power and relativistic electron fluxes are statistically dependent upon one another. We also estimate that the Pearson correlation is missing between 20 % and 30 % of the statistical dependency between ULF wave power and relativistic electron fluxes. Thus, the Pearson correlation underestimates the impact of ULF waves on energetic electron fluxes. However, we find that observed enhancements in relativistic electron fluxes correlate modestly, both linearly and non-linearly, with the ULF power spectrum when compared with values found in previous studies (Simms et al., 2014) and with correlational values found between seed electrons and ULF wave power for the same case events. Our results are indicative of the importance of incorporating data analysis tools that can quantify linear and non-linear interdependencies of various solar wind drivers.Peer reviewe

Using mutual information to investigate non-linear correlation between AE index, ULF Pc5 wave activity and electron precipitation

In this study, we use mutual information from information theory to investigate non-linear correlation between geomagnetic activity indicated by auroral electrojet (AE) index with both the global ultra low frequency (ULF) Pc5 wave power and medium energy (>= 30 keV) electron precipitation at the central outer radiation belt. To investigate the energy and magnetic local time (MLT) dependence of the non-linearity, we calculate the mutual information and Pearson correlation coefficient separately for three different energy ranges (30-100 keV, 100-300 keV and >= 300 keV) and four different MLT sectors (0-6, 6-12, 12-18, 18-24). We compare results from 2 years 2004 and 2007 representing geomagnetically more active and less active years, respectively. The correlation analysis between the AE index and electron precipitation shows a clear MLT and energy dependence in both active and quiet conditions. In the two lowest energy ranges of the medium energy electrons (30-100 keV and 100-300 keV) both non-linear correlation and Pearson correlation indicate strong dependence with the AE index in the dawn sector. The linear dependence indicated by the Pearson correlation coefficient decreases from dawn to dusk while the change in the non-linear correlation is smaller indicating an increase in the non-linearity from dawn to dusk. The non-linearity between the AE index and electron precipitation is larger at all MLT sectors except MLTs 6-12 during geomagnetically more active year when larger amount of the activity is driven by interplanetary coronal mass ejections (ICMEs) compared to lower activity year with high speed stream (HSS) and stream interaction region (SIR) driven activity. These results indicate that the processes leading to electron precipitation become more non-linear in the dusk and during geomagnetically more active times when the activity is driven by ICMEs. The non-linearity between the AE index and global ULF Pc5 activity is relatively low and seems not to be affected by the difference in the geomagnetic activity during the 2 years studied.Peer reviewe

Clonal hematopoiesis in patients with rheumatoid arthritis

Peer reviewe

Somatic mutations and T-cell clonality in patients with immunodeficiency

Common variable immunodeficiency (CVID) and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is, however, implicated. To study whether somatic mutations in CD4(+) and CD8(+) T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset CVID and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2,533 immune-associated genes from CD4(+) and CD8(+) cells. Deep T-cell receptor b-sequencing was used to characterize CD4(+) and CD8(+) T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in CVID, and 48% in controls. Clonal hematopoiesis-associated variants in both CD4(+)and CD8(+) cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immuneand proliferative functions, such as STAT5B (2 patients), C5AR1 (2 patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, CVID patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4(+) and CD8(+) cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.Peer reviewe

Äärimmäiset avaruussäämyrksyt, niiden vaikutukset ja varautuminen

Tässä hankkeessa kerättiin tietoa äärimmäisen voimakkaiden avaruussää-myrskyjen vaikutuksista erilaisiin teknisiin järjestelmiin. Selvitykseen osallistuivat Ilmatieteen laitos, Helsingin yliopisto (HY, Avaruusfysiikan tutkimus) ja Change in Momentum -yritys. Raportissa esitellään laajasta kirjallisuustutkimuksesta kerättyä tietoa voimakkaista myrskyistä ja tietokonesimulaatioiden tuloksia. Raportin loppuosassa käsitellään avaruussäämyrskyihin liittyviä suoria ja välillisiä yhteiskunnallisia riskejä, kuvataan verrokkimaiden kansallisten riskiarvioiden tuloksia jaesitellään varautumisharjoituksiin soveltuva äärimmäisen avaruusmyrskyn skenaario. Kirjallisuustutkimuksessa kiinnitettiin erityistä huomiota avaruus-säämyrskyjen aiheuttamiin ongelmiin sähkönjakelujärjestelmissä niiden laajojen kerrannaisvaikutusten vuoksi. Nopeat vaihtelut Maan magneetti-kentässä synnyttävät jakelujärjestelmiin haitallisia geomagneettisesti indusoituneita (GI) virtoja. Äärimmäisten myrskyjen aikaan saattaa esiintyä jopa kolme kertaa suurempia magneettikentän aikaderivaattoja Euroopassa mitattuihin arvoihin verrattuna. Haittavaikutuksille altis alue ulottuu Keski- ja Etelä-Eurooppaan asti. Meidän tulee siis varautua myrskyjen aiheuttamiin välillisiin vaikutuksiin esim. kansainvälisten toimitusketjujen ongelmien seurauksena, vaikka Suomen sähkönjakelujärjestelmän GI-virtojen sietokyvyn tiedetään olevan hyvä. Koska geomagneettisia myrskyjä riittävän tarkasti kuvaavat aikasarjat ovat verrattain lyhyitä (<150 vuotta), tilastollisissa arvioissa esiintymistodennäköisyyksille esiintyy vielä paljon vaihtelua. Kirjallisuudessa annetut arviot yleisesti vertailukohteena käytetyn vuoden 1859 Carrington-myrskyn kaltaisen ääritapahtuman todennäköisyy-delle seuraavan 10 vuoden sisällä vaihtelevat välillä 0,5–20 %. Hankkeessa testattiin ensimmäistä kertaa Helsingin yliopiston Vlasiator-simulaatiota avaruussäämyrskyjen mallinnuksessa erityisesti satelliittien toimintaympäristöön liittyen. Suurteholaskentaa vaativa Vlasiator on maailman ainoa mallinnustyökalu, joka kattaa koko lähiavaruuden ja kuvaa tarkasti avaruusplasman ionien vaikutuksen myrskyjen kehittymiseen. Simulaatiot osoittivat, että äärimmäisten myrskyjen aikaan geostationaariset ja navigointi-satelliitit menettävät ajoittain magnetosfäärin antaman suojan Auringon hiukkaspurkauksia vastaan. Geostationaaristen satelliittien hiukkasmittausten perusteella HY:n tutkijat arvioivat myös, että korkeaenergiaisten elektronien vuot saattavat olla äärimmäisissä tilanteissa 1–3 kertaluokkaa suuremmat kuin aiempien myrskyjen aikana mitatut satelliittiteknologialle ongelmia aiheuttaneet vuot. Tässä hankkeessa vuosina 2021–2022 tehtyjä Vlasiatorajoja ja muuta tutkimustyötä tarkennetaan ja laajennetaan Suomen Akatemian rahoittamassa “Preparing for the most extreme space weather” -hankeessa vuosina 2020–2023.In this project, information about extreme space weather storms and their impacts on different technological systems was collected by Finnish Meteorological Institute, University of Helsinki (UoH, Space Physics Research), and Change in Momentum company. The report presents findings from a wide literature study addressing strong space weather storms and results from computer simulations. Latter part of the report discusses direct and indirect societal risks due to extreme storms, describes national risk assessments of some reference countries, and presents a storm scenario that can be used in tabletop exercises. The literature study focused on storm impacts on power transmission as they imply indirect effects in several other systems of high societal importance. Rapid variations in Earth’s magnetic field drive harmful Geomagnetically Induced Currents (GIC) into power networks. During extreme storms the time derivatives of geomagnetic field can be even 3 times larger than measured values in Europe. The impacted area covers also Mid- and South-European latitudes. Although Finland’s power transmission system in known to be resilient against GIC, we should be prepared to tackle indirect GIC-impacts that may appear e.g. as breaks in critical supply chains. Statistical estimates for the occurrence rates of extreme storms show large variability, because time series of accurate enough magnetic field measurements are relatively short (<150 years). Literature suggests that the occurrence probability for a storm of similar intensity as the famous Carrington extreme storm in 1859 to happen in forthcoming 10 years is in the range of 0,5–20%. The Vlasiator high performance computing code of UoH was tested for the first time in simulations of extreme space weather activity in this project. Simulation results were analysed with the focus on satellites’ plasma environment. Vlasiator is the only modelling tool in the world that can handle near-Earth plasma processes globally and describe accurately the crucial ion physics contribution to storm evolution. Simulation results show that geostationary and navigation satellites can occasionally loose the protection by Earth’s magnetosphere against hostile solar particle bursts during extreme activity. Furthermore, statistical analysis of geostationationary particle data by the UoH team suggests that fluxes of high energy electrons can be 1–3 orders of magnitude larger than the fluxes which have caused problems for satellites during previous storms. Vlasiator-simulations and other research conducted in this project (2021–2022) will be continued and expanded in the project “Preparing for the most extreme space weather” funded by the Academy of Finland (2020–2023)

Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+T Lymphocyte Signature

Rheumatoid arthritis (RA) is a complex autoimmune disease targeting synovial joints. Traditionally, RA is divided into seropositive (SP) and seronegative (SN) disease forms, the latter consisting of an array of unrelated diseases with joint involvement. Recently, we described a severe form of SN-RA that associates with characteristic joint destruction. Here, we sought biological characteristics to differentiate this rare but aggressive anti-citrullinated peptide antibody-negative destructive RA (CND-RA) from early seropositive (SP-RA) and seronegative rheumatoid arthritis (SN-RA). We also aimed to study cytotoxic CD8+ lymphocytes in autoimmune arthritis. CND-RA, SP-RA and SN-RA were compared to healthy controls to reveal differences in T-cell receptor beta (TCR beta) repertoire, cytokine levels and autoantibody repertoires. Whole-exome sequencing (WES) followed by single-cell RNA-sequencing (sc-RNA-seq) was performed to study somatic mutations in a clonally expanded CD8+ lymphocyte population in an index patient. A unique TCR beta signature was detected in CND-RA patients. In addition, CND-RA patients expressed higher levels of the bone destruction-associated TNFSF14 cytokine. Blood IgG repertoire from CND-RA patients recognized fewer endogenous proteins than SP-RA patients' repertoires. Using WES, we detected a stable mutation profile in the clonally expanded CD8+ T-cell population characterized by cytotoxic gene expression signature discovered by sc-RNA-sequencing. Our results identify CND-RA as an independent RA subset and reveal a CND-RA specific TCR signature in the CD8+ lymphocytes. Improved classification of seronegative RA patients underlines the heterogeneity of RA and also, facilitates development of improved therapeutic options for the treatment resistant patients