Sammanfattning Sedan sjukdomen Covid-19s uppdykande i början av 2020 har forskning pågått för att karaktärisera sjukdomen ur alla tänkbara vinklar för att på kortast möjliga tid bereda väg för ett fungerande botemedel. Effektiva läkemedel som kan minska risken för allvarligt sjuka patienter att avlida i sjukdomen behövs; många preparat har föreslagits och testats och i Sverige har hittills två läkemedel godkänts för Covid-19. Ett av dessa är kortikosteroiden dexametason som godkänts för Covid-19-patienter i behov av syrgas eller respirator. Syftet med detta arbete var att undersöka hur effektiv kortikosteroidbehandling av svårt sjuka Covid-19-patienter var i jämförelse med standardbehandling utan kortikosteroider. En litteratursökning gjordes i PubMed och i covid-nma efter randomiserade kliniska studier av kortikosteroider jämfört med standardbehandling till patienter med Covid-19. Ur resultatet som inkluderade 7 kontrollerade studier med 7784 svårt sjuka patienter från 11 länder och fem kontinenter, gjordes en sammanvägning av den primära utfallsvariabeln mortalitet 28 dagar efter randomisering varpå relativ risk (RR) räknades ut individuellt per studie och sammanvägt för alla studier. Analysen gjordes också med den mest dominanta studien borträknad. Vidare utforskades möjliga samband mellan sjukdomsgrad och effektstorlek, dels genom ett försök till metaregression av studiemortalitet och andningshjälpsnivå mot RR som var inkonklusivt, men också genom att leta efter speciellt sjuka undergrupper i studierna. 3 studier rapporterade mortalitet efter 28 dagar, 1 studie rapporterade mortalitet efter 21 dagar, 2 studier rapporterade död på sjukhus och en studie rapporterade död efter 15 dagar. Testade preparat var dexametason, hydrokortison och metylprednisolon. Av 2885 patienter som randomiserats till någon kortikosteroid, dog 739, medan det av de 4899 som randomiserats till standardbehandling dog 1347 patienter vilket gav en icke signifikant RR på 0,93 (95% CI 0,86–1,01). Vid borträkning av den största studien som bestod av relativt friskare patienter erhölls en starkare och signifikant effekt med RR 0,80 (95% CI 0,70–0,92) baserat på 257 av 781 döda i steroidgrupperna jämfört med 237av 578 döda i någon kontrollgrupp med standardbehandling. Resultatet var även i linje med analysen av olika sjuka undergrupper från största studien som visade bäst effekt hos de med invasiv mekanisk andningshjälp (absolut riskreduktion 12,1%) samt en icke signifikant försämring hos de friskaste patienterna utan syrgasbehov. Sammantaget tyder dessa resultat på att behandling av svårt sjuka Covid-19-patienter med kortikosteroider minskar mortaliteten efter 28 dagar. Dessutom ger studien en stark indikation på att bästa effekten fås om kortikosteroiderna ges till patienter där den systemiska inflammationen i lungorna nått en gasutbyteshämmande nivå / ABSTRACT Since the emergence of the new corona virus disease, Covid-19, much research effort has gone into characterising every possible angle of the disease to pave the way for a possible cure in the shortest possible time. Effective therapies are needed that will reduce the risk of dying for severely to critically ill Covid-19 patients. Many existing therapies have been suggested, tested and repurposed for the treatment of Covid-19 but so far only two drugs have been approved in Sweden for this indication, namely the antiviral drug remdesivir and the corticosteroid dexamethasone. Corticosteroids are both immunosuppressive and anti-inflammatory and when they were administered previously for severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS) and influenza they were found to increase the time to rid the body of virus. The purpose of this study was to investigate evidence found in the research literature of how effective corticosteroids are in reducing the risk of dying as compared to standard treatment with no corticosteroids when administered to hospitalised patients with severe Covid-19. A literature search was made in the PubMed and covid-nma databases for randomized clinical studies of corticosteroids versus standard treatment to patients with Covid-19. The result included 7 studies with 7784 patients from 11 countries and 5 continents which all reported death as an outcome in groups that were receiving corticosteroids compared to groups that were receiving standard care. The studies used one of the following corticosteroids as intervention: dexamethasone, methylprednisolone and hydrocortisone in different doses. In the groups receiving standard care, 1347 patients out of 4899 died while in the corticosteroid groups 739 of 2885 patients died. When doing a statistical calculation these figures indicated that the risk of dying when getting corticosteroids was 93% of the risk when not getting corticosteroids, however the difference was not statistically significant. After omitting the largest study from the material, that contributed the absolute majority of total participants, who were deemed relatively healthy or well taken care of, the results were instead that 257 out of 781 died in the steroid groups and 237 of 578 died in the control groups. This later comparison among supposedly sicker patients, gave a statistically significant 8,1% lower absolute risk of dying in the corticosteroid groups; an effect that could also be expressed as for every 25 patients treated, 2 more lives would be saved. A further control of a more severely sick subgroup of patients from the largest study, in need of invasive mechanical ventilation, revealed an absolute reduction of the risk of dying when given corticosteroids of 12,1%. This group showed the most effectful response to the administered corticosteroids in this study which could also be expressed as 1 more life saved for every 8 patients treated. Another sub group analysis of the patients from the largest study that were not in need of any type of oxygen support, indicated on the other hand a possible harm of corticosteroids. This potentially harmful effect was however not statistically significant. In summary, the results of this study imply that administration of corticosteroids to patients with severe Covid-19 will reduce the risk of dying. The greatest effect is seen in those patients that has reached a level of illness were the gas exchange in the lungs is impaired by the inflammation. Furthermore, caution must be taken not to introduce harm by giving corticosteroids to patients with milder disease in which the immunosuppressive properties of the drug could lead to unintended worsening of the illness.

Introduction: Incident reporting systems have been implemented in health care for over a decade and contain reports of critical incidents (CI). These must be analyzed in order to suggest, implement and evaluate solutions for minimizing the risk of future CIs to occur, thereby increasing patient safety. Drug-related CIs (DRCI) are one type of CI which may represent up to 1/3rd of all CIs, therefore this CI-type is characterized in this study. Aim: To categorize and characterize DRCIs reported in the Critical Incident Reporting System North Rhine-Westphalia (CIRS-NRW). Materials & Methods: In this explorative, retrospective, descriptive study, 553 reports from the CIRS-NRW, reported between the 1st of January 2019 and the 15th of September 2021, were analyzed. These were categorized by setting, medication use process stage, ATC-code, patient age and look-alike, sound-alike (LASA), and then analyzed via descriptive statistics. Various subgroup analyses were also conducted. Results: DRCIs occurred mostly in the hospital (48,5%) and pharmacy (40,7%) settings, during the prescribing (33,8%) and administration (33,5%) of drugs and the ATC-codes N02 (9,4%), B01 (6,9%) and N05 (5,4%) were commonly involved. Patient age contained >50% missing data and LASA was involved in 16,5% of DRCIs. Subgroups were often small, likely resulting in low statistical power. Conclusion: By successfully characterizing the DRCIs, some potential areas of improvement for reducing future DRCIs were highlighted, however there are many more variables of relevance for patient safety than those analyzed in this study, underlining the need for further studies characterizing more DRCIs including additional variables.

Inledning: Sjuka barn behöver anpassad vård och säkra, effektiva och väldokumenterade läkemedel. Förskrivning och uttag av preparat för pediatriska populationen ökar, men en tydlig uppskattning på problematik finns inte. Problem kan uppstå, när en lämplig beredning saknas, när redan registrerade läkemedel saknar avdelade doser för barn eller är tillgängliga enbart som en tablett med vuxen dos. Varje barn sägs vara en individ med unika läkemedelsomsättning, metabolism och biverkningspanorama, vilket komplicerar behandling. Lösningen på detta är i många fall ett extemporeläkemedel eller ett licenspreparat, men långa ledtider och dålig tillgänglighet kan medföra svårigheter att kunna ge rätt terapi. Syftet med denna studie är att i) kartlägga behov och befintliga lösningar, ii) testa handhållna pulverdispenser (HPD) Quantos, som en lämplig metod för fasta beredningar för att tillhandahålla individuella läkemedelsdoser till barn i de fall godkända läkemedel inte räcker.  Metod: Databassökning, intervjuer av hälso-sjukvårdspersonal, samt laborativt arbete för att omformulera registrerade läkemedel i tablettformer till individanpassade doser i hårdgelatin-kapslar med hjälp av Mettler-Toledos handhållna pulverdoseringsinstrument HPD Quantos. Resultat: Litteraturstudien och intervjuer överensstämmer med varandra: behov av barnanpassade läkemedel finns. HPD Quantos kan vara en alternativ metod för fasta beredningar för att tillhandahålla mängderför uppdosering med en femte- och/ eller en sjättedel av en tablett. Slutsats: För att ombesörja behoven för barnanpassade doser på ett sjukhus, måste HPD Quantos automatiseras till en inbyggd doseringsstation. Detta kommer att säkerställa dosering, dölja obehaglig smak, samt minska arbetsmiljörisken vid exponering av toxiska läkemedel.

In healthcare, vulnerable populations that are using medications with a narrow therapeutic index and wide interpatient PK/PD (pharmacokinetic/pharmacodynamic modelling) variability are increasing. As such, variable dosage regimens may result in severe therapeutic failures or adverse drug reactions (ADR). Improved monitoring of patient response to medication and personalization of treatment is therefore warranted. Precision dosing aims to individualize drug regimens for each patient based on independent factors obtained from a patient’s clinical records. Personalization of dosing increases the accuracy and efficiency of medication delivery. This can be achieved through utilizing the wide range of Electronic Health Records (EHR) contain the patients’ medical history, diagnoses, laboratory test results, demographics, treatment plans, biomarker data; information that can be exploited to generate a patient-specific treatment regimen. For example, Fast Healthcare Interoperability Resources (FHIR) is an existing healthcare standard that provides a framework on which semantic exchange of meaningful clinical information can be developed such as using an ontology as a decision support tool to achieve precision medicine. The purpose of this thesis is to make an investigation of the feasibility of interoperability in EHR and propose an ontology framework for precision dosing using currently existing health standards. The methodology involved carrying out of semi-structured interviews from professionals in relevant areas of expertise and document analysis of already existent literature, a precision dosing ontology framework is developed. Results show key tenants for an ontology framework and drugs and their covariates. The thesis therefore advances to investigate how data requirements in EHR systems, IT platforms, implementation, and integration of Model Imposed Precision Dosing (MIPD) and recommendations have been evaluated to cater to interoperability. With modern healthcare striving for personalized healthcare, precision medicine would offer an improved therapeutic experience for a patient.

Syfte: Syftet med examensarbetet var att undersöka individers kunskap om symboler för godkända apotek samt hur en sådan märkning och andra faktorer påverkar deras val av apotek ur ett säkerhetsperspektiv. Introduktion: I en kartläggning av Läkemedelsverket från 2008 hittades 51 illegala webbsidor som riktade sig till svenska apotekskunder. Dessa webbsidor sålde illegalt receptbelagda läkemedel utan krav på något recept från sina kunder. Att handla på illegala internetapotek kan utgöra risker såsom kontaminerade läkemedel, bristande information om läkemedlet eller att läkemedlet inte levereras. För att minska risken för att apotekskunder ska råka handla på illegala internetapotek finns det två symboler som används för att kontrollera internetapotek, en skapad av Läkemedelsverket (figur 1) och en skapad av Europeiska kommissionen (figur 2). Tanken är att kunden ska trycka på en av symbolerna på apotekets hemsida som sedan tar apotekskunden till Läkemedelsverkets lista på godkända internetapotek. Finns apotekets namn och webbadress i listan så är apoteket godkänt, gör det inte det så finns det en risk att webbsidan är ett illegalt internetapotek och bör därför inte handlas från. Material och metod: Ett elektroniskt frågeformulär med 10 frågor (bilaga A) togs fram utifrån syftet och skickades ut genom den sociala plattformen ”Facebook” genom studentens Facebook-konto. Formuläret innefattade frågor om vilka faktorer som får respondenter att välja internetapotek ur ett säkerhetsperspektiv och respondenternas kännedom om de två symbolerna för kontroll av internetapotek. Resultatet analyserades på gruppnivå så att ingen enskild kunde identifieras. Resultat och diskussion: Undersökningen visade att en majoritet av respondenterna (n=44, 59 %) hade sett den svenska symbolen för godkänt apotek (figur 1) från Läkemedelsverket. Dock var det en majoritet som inte visste vad den betydde (n=57, 77 %). När det gäller EU-symbolen för godkänt internetapotek (figur 2), visade sig att en majoritet av respondenterna varken hade sett den (n=58, 78 %) och ännu fler visste inte vad den betydde (n=62, 84 %). Respondenterna i studien kontrollerar apotek på lite olika sätt såsom att göra en egen bedömning om internetapoteket verkar säkert (n=21, 51 %) eller att de har sett apoteket i någon form av reklam (n=17, 41 %) (tabell II). För vissa var det dock inget de tänker på (n=10, 24 %) (tabell II). Slutsats: Examensarbetets slutsats är att majoriteten av respondenterna hade sett den svenska symbolen för godkända apotek men visste inte vad den innebär. EU-symbolen för godkända apotek hade få av respondenterna sett och ännu färre som visste vad den innebär. De vanligaste faktorerna för att välja internetapotek från ett säkerhetsperspektiv hos respondenterna var genom att de själva bedömde ifall ett internetapotek verkar säkert eller att de valde apotek som de tidigare sett från reklam. För vissa respondenter var det inte något de hade tänkt på direkt. / Aim: The aim of the degree project is to examine individual’s knowledge about symbols for approved pharmacy and how such a marking and other factors affect their choice of pharmacy from a safety perspective. Introduction: In a survey made by the Swedish Medical Products Agency (MPA) from 2008, 51 illegal websites targeting Swedish pharmacy customers were found. These websites illegally sold prescription pharmaceuticals without the requirement of a prescription from their customers. Shopping on illegal internet pharmacies can have great risks like contaminated drugs, lack of information about the drugs or that the drugs never gets delivered. To lower the risk that pharmacy customers accidently buys medications from the illegal online pharmacies, two symbols have been created for Swedish pharmacy customers, one by the MPA (figure 1) and one by the European Commission (figure 2). The idea is that the customer is supposed to click on one of the symbols on an online pharmacy’s website which is linked to a list for approved online pharmacies at the website of the MPA. If the customer finds the name and web address of the pharmacy on that list, the customer will know that the pharmacy is approved. But if the name and address isn’t found on the list, the pharmacy can be illegal, and the customer should avoid from shopping from the pharmacy. Material and methods: An electronic questionnaire with 10 question (Appendix A) was created in regard of the aim and sent out via the social platform “Facebook” through the students Facebook account. The survey included questions about which factors, from a security perspective, that influence the respondents to choose an online pharmacy and the respondents’ knowledge about the two symbols for controlling if an online pharmacy is approved. The results were analysed at a group level so that no individuals could be identified. Results and Discussion: The survey showed that a majority of the respondents had seen the Swedish symbol for approved pharmacy (figure 1) from the MPA (n=44, 59 %). However, a majority did not know what it means (n=57 or 77 %). Regarding the EU-symbol for approved pharmacy (figure 2), it turned out that most of the respondents had not seen it (n=58, 78 %) and even more didn’t know what it means (n=62, 84 %). The respondents in the study controlled pharmacies in different ways, for example making their own assessment if an online pharmacy seems safe (n=21, 51 %) or that they choose an online pharmacy that they have seen on some sort of commercial (n=17, 41 %) (Table II). For some it wasn’t something they thought about (n=10, 24 %) (Table II). Conclusions: The conclusion is that most of the respondents had seen the Swedish symbol for approved pharmacy but did not know what it means. Few respondents had seen the EU-symbol for approved pharmacy and even fewer knew what it means. The most common factors influencing the respondents’ choice of a pharmacy, from a security perspective, was by making their own assessment if the online pharmacy seems safe or choose a pharmacy which they have seen from a commercial. For some of the respondents, it wasn’t something they considered when choosing pharmacy.

Background: Oral contraceptives are common among female athletes. Still, its effects on athletic performance are poorly investigated. Research in the area has increased in recent years. However, the study qualities and designs are often insufficient and with small sample sizes. Women are currently underrepresented in sport research, and to recruit more women in future studies and to facilitate female athletes’ choices about contraceptives, the impact of oral contraceptives on performance must be better understood. Aim: The aim was to investigate whether monophasic, combined oral contraceptive phases affected maximal muscle strength, anaerobic performance and the corresponding blood lactate response, or perceived mental and physical energy level among young women. Method: The study used a cross-over design where six participants were tested on two occasions. The participants were healthy women between 18 and 29 years old who had beenusing monophasic combined oral contraceptives for at least three months prior to the study. No criteria for training level was set. The Isometric mid-thigh pull (N) was used as an indicator ofmaximal muscle strength; and the Wingate anaerobic test (W) measured anaerobic performance and power with corresponding blood lactate levels (mmol/L) measured at 0, 3 and 5 minutes after termination of the test. The participants rated their current physical and mental energy level on both test occasions using a visual analog scale (0-10). Statistical analyses were madeusing Wilcoxon signed-ranked test. Results: Nine participants were recruited, of which six performed tests on both occasions. The participants had a mean (SD) age of 22.3 (1.8) years, a BMI of 23.3 (2.6) and all reached WHO’sphysical activity recommendations. No statistically significant differences in muscle strengthor anaerobic performance were found regarding peak force (p=0.60), peak power (p=0.35) oraverage power (p=0.60) between oral contraceptive phases. Neither were there any differencesin the blood lactate response to the Wingate test directly after (p=0.92), 3 minutes after (p=0.17) or 5 minutes after (p=0.60) the test. No differences in perceived mental energy level (p=0.35)or perceived physical energy level (p=0.17) between oral contraceptive phases were evident. Conclusion: Oral contraceptive phases did not affect maximal muscle strength, anaerobicperformance, blood lactate response or perceived mental or physical energy levels. Accordingly, there is no need to adapt training to oral contraceptive phases and women can berecruited in future research without consideration of oral contraceptive phases.

Glioblastoma is the most aggressive type of primary tumor in the central nervous system (CNS tumors). It is hard to treat and has a poor prognosis for survival. Primary CSN tumors occur in approximately 1400 adults in Sweden every year and is the third most common cause of cancer-related deaths in individuals between 15-24 years of age.   There is no prophylaxis for primary CNS tumors. The causes of most CNS-tumors are unknown, but there are several risk factors that have been identified. Both heredity and environmental factors are likely to come into play, but clinical data does not suggest any convincing evidence of CNS tumor formation. Some cases of CNS tumors are related to known genetic conditions that cause rare syndromes and have an increased risk of getting a brain tumor.   The treatments for glioblastoma are surgery, radiotherapy, chemotherapy, TTField treatment and immunotherapy. Immunotherapy is a type of cancer treatment that uses the patient’s immune system to fight CNS tumors. New cancer immunotherapies, such as dendritic cell (DC)-based vaccines are under development to enhance anti-tumor presentation and to prime anti-tumor T-cell responses.   The objective of this study was to investigate the efficacy of DC vaccines for the treatment of glioblastoma.    Seven clinical studies from PubMed were found after searching in the Pubmed database, and filtering through the inclusion and exclusion criteria. All seven studies explored the efficacy of DC vaccines on overall survival and progression-free survival for patients with glioblastoma. In addition to investigating the safety and adverse events, the clinical trials evaluated the immune response to the DC vaccines against glioblastoma.   Combining standard of care (SOC) with DC vaccines prolonged the overall survival by several months compared to SOC alone. Severe adverse reactions (grade 3) were reported in two studies, while the rest of the studies showed that patients tolerated the DC vaccines and had only mild grade 1-2 adverse events. Half of the studies correlated prolonged median survival or progressions- free survival with immune response.   Further research is required to compare the efficacy of DC vaccines and other immunotherapies in order to conclude whether DC vaccines are a feasible effective treatment of glioblastoma in the future.