Pharmacoepidemiology and health economics of adherence to pharmaceutical fracture prevention

Background: Osteoporosis is a disease characterized by weak bone, affecting hundreds of millions of people worldwide, predominantly postmenopausal women. The main clinical consequence of the disease is bone fractures and the lifetime risk of any fracture has been estimated at ~55% in Norwegian women. Hip and vertebral fractures are the two most serious fracture types, associated with substantial pain, disability, and even death. Even though there is consensus that patients at high risk of fracture should be treated, there is still a troubling treatment gap that shows few signs of closing. Only 6.6% of untreated patients receive treatment after their first fracture and there are ~225,000 untreated individuals with a bone mineral density indicative of osteoporosis in Sweden. An equally noteworthy aspect of undertreatment is poor adherence (compliance and persistence) to treatment, i.e. how patients and physicians adhere to dosing instructions and treatment regimens. Many patients stop filling prescriptions at pharmacies prematurely (refill non-persistence) and this is a cause for concern with respect to effective fracture prevention. There are also reports that dispensings at pharmacies are too few and far between to provide adequate drug exposure (measured as refill compliance). Oral alendronate, a bisphosphonate, constitutes ~80% of all osteoporosis treatments and is generally recommended for 3-5 years. Treating osteoporosis have in most industrialized countries been estimated to be cost-effective (compared with no treatment) but this depends on several factors, such as the risk of the patient population, drug costs, treatment effectiveness, and the treatment alternatives being compared. Treatment adherence is often not factored into such cost-effectiveness analyses. Objectives: This thesis aims at addressing pharmacoepidemiologic and health economic aspects of poor compliance and persistence to osteoporosis treatment by both establishing the extent of the problem and consequences for fracture risk in a Swedish setting, as well as investigating how it can be incorporated into the health economic framework to inform reimbursement decisions and regional priorities for recommended prescription standards. The topics of health-economic value or treatment persistence are by no means specific to the Swedish setting. Therefore, even though the included publications are based on Swedish data, the background and findings are also often put in an international context, or entirely without reference to geography. Methods & papers: Three of the articles used Swedish register data on pharmacy dispensings, diagnosis codes, and mortality. Repeat dispensings at pharmacies by 57,000 individuals were used to estimate refill persistence and refill compliance as an approximation of true drug exposure. Paper I investigated the proportion of patients starting an osteoporosis treatment that stopped their treatment prematurely at different time points, as well as the implications on the risk of fracture in groups stratified by refill persistence. Paper II addressed how automatic generic substitution (for off-patent medication) influence persistence to treatment of oral bisphosphonates. A natural experiment was devised for the years 2006-2009 where an off-patent medication was compared to an on-patent medication to isolate the effect of generic substitution. The effect on persistence for patients getting their first medication refill substituted at the pharmacy was also investigated. Paper III, amended with a new analysis in a larger dataset, investigated the residual effect after treatment with bisphosphonates on fracture risk and explored whether a healthy adherer effect (i.e. that patients with an inherently lower fracture risk stay longer on treatment) confounds the association between refill persistence and residual anti-fracture effect. Paper IV proposes a health economic simulation model framework for incorporating adherence and studying the important drivers of cost-effectiveness in this context. Main conclusions: • Refill persistence to typical oral osteoporosis medication estimated from pharmacy dispensing in Sweden is poor, with ~50% stopping treatment within 12 months. Prescription refill gaps among persistent patients appears to be a margnial problem, with 96% of patients having access to >80% of intended doses. • Poor refill persistence to osteoporosis treatments is associated with an increased fracture risk in an exposure-dependant manner. • Automatic generic substitution of alendronate tablets at pharmacies was likely causing reduced treatment persistence to treatment during 2006- 2009. Patients who had their alendronate product substituted at the first prescription refill had 25% higher risk of stopping their treatment. This topic should be revisited in more recent data and for other therapeutic areas. • It is likely that treatments shorter than 6 months with oral bishposphonates has little effect on fracture risk. • Oral bisphophonates taken for at least 12 months may confer a residual effect of 20-35% on the risk of any fracture for up to 5 years after stopping treatment. It is not clear if and how such a residual effect wanes with time after stopping treatment. The health economic implications of residual effect can be considerable, depending on the context. • There is a statistically significant inverse relationship between time on bisphosphonate treatment and post-treatment fracture risk. This finding supports an assumption that the magnitude of a residual effect depends on the preceding time on treatment with bisphophonates in health-economic evaluations. • Incorporating treatment adherence into a health economic evaluation in osteoporosis can have a substantial impact, but is context specific. The choice of accounting for or disregarding adherence to treatment may have an impact on both treatment recommendations, priorities, reimbursement, and prices of treatments for osteoporosis. Poor persistence to osteoporosis treatments causes increased morbidity and mortality. Improving persistence to osteoporosis treatments would confer substantial health benefit for both patients and society. The clinical and health-economic consequences of persistence to osteoporosis treatments should not be disregarded when setting priorities and drug prices

The effect of turbulent velocity fluctuations on the convective heat transfer to droplets subjected to evaporation and thermolysis

The effect of turbulent velocity fluctuations on the convective heat transfer to single droplets in a turbulent channel flow are investigated numerically. It is found that for properties relevant to typical liquid spray applications, the convective heat transfer is enhanced with increasing droplet size and bulk Reynolds number. The combined effect of convective heat transfer enhancement and increased driving forces for heat and mass transfer due to droplet dispersion is thereafter investigated for a commercial spray application. The probability distribution functions of droplet properties in the spray are found to be significantly affected by the presence of turbulent velocity fluctuations in the carrier phase

The Effect of Turbulent Velocity Fluctuations on the Convective Heat Transfer to Droplets Subjected to Evaporation and Thermolysis

Abstract. The effect of turbulent velocity fluctuations on the convective heat transfer to single droplets in a turbulent channel flow are investigated numerically. It is found that for properties relevant to typical liquid spray applications, the convective heat transfer is enhanced with increasing droplet size and bulk Reynolds number. The combined effect of convective heat transfer enhancement and increased driving forces for heat and mass transfer due to droplet dispersion is thereafter investigated for a commercial spray application. The probability distribution functions of droplet properties in the spray are found to be significantly affected by the presence of turbulent velocity fluctuations in the carrier phase

Results From a Network Meta-Analysis

CONTEXT: Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD) affecting mineral and bone metabolism and characterized by excessive parathyroid hormone (PTH) production and parathyroid hyperplasia. OBJECTIVE: The objective of this analysis was to compare the efficacy and adverse effects of extended-release calcifediol (ERC) and paricalcitol (PCT) by assessing their effect on the biomarkers PTH, calcium, and phosphate in patients with non-dialysis CKD (ND-CKD). METHODS: A systematic literature research was performed in PubMed to identify randomized control trials (RCTs). Quality assessment was done with the GRADE method. The effects of ERC vs PCT were compared using random effects in a frequentist setting. RESULTS: Nine RCTs comprising 1426 patients were included in the analyses. The analyses were performed on 2 overlapping networks, due to nonreporting of outcomes in some of the included studies. No head-to-head trials were identified. No statistically significant differences in PTH reduction were found between PCT and ERC. Treatment with PCT showed statistically significant increases in calcium compared with ERC (0.2 mg/dL increase; 95% CI, -0.37 to -0.05 mg/dL). No differences in effects on phosphate were observed. CONCLUSION: This network meta-analysis showed that ERC is comparable in lowering PTH levels vs PCT. ERC displayed avoidance of potentially clinically relevant increases in serum calcium, offering an effective and well-tolerated treatment option for the management of SHPT in patients with ND-CKD.publishersversionpublishe

Microfluidic Preparation and Transport of Long DNA using Pillar Arrays

This thesis presents a set of microfluidic tools and experimental studies for preparing (> 20 kbp) for genetic analysisas well as the transport of high-concentration, long-DNA solutions in pillar arrays.Long-DNA sample preparation with conventional gel-based techniques is slow (tens of hours to days) and laborious. Ifsize-selective separation is to be achieved, it is also expensive. Long-DNA preparation is essential for detectinggenetic sequences that ranges above kilobase pairs such as large scale structural variations. These can in turn beimportant for diagnosing genetic diseases.Deterministic lateral displacement (DLD) has been used to prepare the long DNA. DLD is a continuous microfluidicseparation method. Long-DNA separation in DLD has previously been thought to be limited to very low flow velocities(up to 40 μm/s) and thus low throughput. In this work, we show that it is possible to displace long DNA up to a meanflow velocity of approximately 34 mm/s. This increases the separation throughput immensely (one to five orders ofmagnitude in throughput compared to other microfluidic techniques) which makes it possible to collect enoughseparated sample after a few minutes to hours, depending on the post-separation analysis method. We explore theeffect of high concentration and show that long-DNA separation can both be enhanced and lessened as aconsequence of concentration-based effects. We also integrate long-DNA isolation in DLD with subsequent surfacestretching of the isolated DNA molecules. Combining the analysis on-chip after the separation eliminates anyproblematic sample transfer steps and allows the analysis to work with dilute samples of only a few hundredmolecules.Novel elastic flow phenomena have been discovered. Large-scale ordered regular DNA waves have been observed toemerge in pillar arrays when trying to increase the throughput of DNA separation in DLD. It is possible that thesewaves could either improve separation or worsen it and thus set the limits for it. A large part of the presented workaimed to understand the emergence and character of these waves. The peaks of these waves consist of high localDNA concentration with the DNA strands stretched and oriented with the wave fronts. These have been found tooccur at high flow velocity, u, and high concentration to overlap concentration ratio (C/C*). We have explored thewave onset in C/C* and u by changing the polymer length, concentration and ionic strength of the buffer. Thesewaves arise together with periodic cycles of growth and shedding of masses of DNA that collect in the pillar gaps inthe flow direction.We also show that the macroscopic and microscopic DNA flow patterns in micro pillar arrays depend highly on thepillar distribution and the pillar shape. By changing the pillar array distribution to hexagonal instead of quadratic, largescalechaotic zig-zag patterns are observed. By changing the distribution to a disordered one, no large-scale flowpattern is observed. We speculate that the induction or avoiding of a large-scale flow pattern could be useful fordifferent degrees of mixing. By changing the pillar shape from circular cross-section to a triangular one, we form largewaves of only one orientation instead of two. The large waves appear in a different orientation depending on the flowdirection. In addition, the microscopic vortex behavior emerges at different flow velocities for the two directions as wellas with different flow resistances. This could be exploited in microfluidic components such as one-way valves orpumps

RBC deformability fractionation and hydrodynamic trapping for studying Plasmodium Falciparum infection

There have been several studies which indicate a preferential invasion towards younger red blood cells (RBCs) for the malarial parasite, P. Falciparum. Knowledge about a preferential mechanism could aid in the development of novel anti-malarial drugs. While the preference in these reports has been studied with density-separation of red blood cells, separating the cells by deformability may be a more accurate method of isolating groups of RBCs with differing age. This thesis has investigated the details of separating RBCs by deformability in the microuidic technique Deterministic Lateral Displacement (DLD). RBCs have been observed to undergo strong deformation in the device but the large size variation of RBCs together with RBC shape transformations inside the shallow channels have interfered with the separation by deformability. Further studies where higher device driving pressures with alternative device designs are utilized and the deformability of the separated cells are benchmarked towards existing techniques are proposed. Furthermore, on-chip invasion of trapped RBCs has been investigated using hydrodynamic trapping arrays. The trapping arrays allow for convenient and highly-controllable investigation of the invasion dynamics. The trapping arrays have been fabricated using replica molding and been used to successfully immobilize RBCs. Trap occupancy rates up to 85% over the span of 14 min have been achieved. On-chip parasitic behavior has been investigated. It involved several complications including the prevention of late-stage parasite rupture due to shape transformation of RBCs into echinocytic (crenated cells) when introduced into shallow PDMS (polydimethylsiloxane) channels. This complication seem to affect the rupturing of late-stage infected RBCs inside the channels. Alternative materials and surface-coating should be explored to minimize any channel-derived artefacts.Mikrofluidisk separation och en-cell fångst av röda blodkroppar Populärvetenskaplig Sammanfattning av Examensuppsats, Oskar Ström Varje år dör en halv miljon människor av malaria 1. Invasionen in i röda blodkroppar av malariaparasiter efter en malariainfektion är central för sjukdomens utveckling. För att kunna studera invasionen har mikroskopiska fällor utvecklats och använts för att fånga in röda blodkroppar. Separering av blodkroppar baserat på mjukhet har också utforskats. Båda teknikerna som använts i projektet bygger på att celler och parasiter förs in i mikrokanaler på ett tunnt glas/plast-chip, ett så kallat “Lab-on-a-chip”. Lab-on-a-chip bygger på att man miniatyriserar funktionerna från ett helt lab till ett litet chip. Sådana chip gör det möjligt att analysera prover och diagnostisera sjukdomar utan att använda sig av kostsamma, komplicerade och stora maskiner som finns i konventionella lab. Chippen kan tillverkas billigt med hjälp av massproduktion och behöver dessutom en ytterst liten provvolym. En droppe blod kan vara det enda som behövs för att kunna analysera blodsjukdomar. Det är mycket vi fortfarande inte vet om malaria, där mikroskopiska parasiter förs in i kroppen via myggbett. Det är oklart hur den dödligaste malariaparasiten, Plasmodium falciparum, väljer vilka röda blodkroppar som den ska invadera väl inne i kroppen. Det finns forskning som tyder på att parasiten föredrar att angripa yngre celler. Ökad kunskap om denna process skulle kunna leda till nya behandlingar och läkemedel mot malaria. Det här projektet har utforskat möjligheterna att dela upp röda blodkroppar i olika åldersgrupper genom att utnyttja det faktum att yngre celler är mjukare än äldre celler 2, 3. Den naturliga storleksvariationen på cellerna har varit ett stort hinder för separation baserad på mjukhet då separeringsmetoden är känslig både för storlek och mjukhet. I framtiden skulle man först kunna separera på storlek för att undvika detta problem. I projektet har också kanaler med mikrofluidiska fällor designats och använts för att fånga in röda blodkroppar för att senare utsätta dem för malariaparasiter. Fällorna fängslar cellerna endast genom att utnyttja de fysikaliska effekter som uppstår när man pumpar vätska innesluten i mikroskopiska kanaler. Olika former på fällorna har studerats där den bästa varianten fyllde 85% av fällorna efter 14 minuter. Under projektets gång visade sig att de grunda kanalerna, tillverkade i polymeren PDMS (Polydimetylsiloxan) hindrade parasiterna från att bryta sig ut ur röda blodkroppar som de naturligt gör i kroppen. Denna effekt (kallad “glas-effekten”) förvandlade nämligen blodkropparna till celler med taggiga utskott, likt igelkottar. Genom att hitta alternativa material för mikrokanalerna skulle denna effekt kunna minskas och det skulle kunna vara möjligt att studera parasiterna i mikrokanaler. I framtiden skulle fällorna även kunna användas till andra ändamål. Bland annat för att studera andra cell-reaktioner (ex. läkemedelsleverans eller partikelgiftighet) under hög kontroll. Referenser 1 World Health Organization. World malaria report 2015. Technical report, 2015. 2 G Pasvol, DJ Weatherall, and RJM Wilson. The increased susceptibility of young red cells to invasion by the malarial parasite plasmodium falciparum. British journal of haematology, 45(2):285295, 1980. 3 Robert Hegner et al. Relative frequency of ring-stage plasmodia in reticulocytes and mature erythrocytes in man and monkey. American Journal of Hygiene, 27(3):690 718, 1938

High-Throughput Separation of Long DNA in Deterministic Lateral Displacement Arrays

Length-based separation of DNA remains as relevant today as when gel electrophoresis was introduced almost 100 years ago. While new, long-read genomics technologies have revolutionised accessibility to powerful genomic data, the preparation of samples has not proceeded at the same pace, with sample preparation often constituting a considerable bottleneck, both in time and difficulty. Microfluidics holds great potential for automated, sample-to-answer analysis via the integration of preparatory and analytical steps, but for this to be fully realised, more versatile, powerful and integrable unit operations, such as separation, are essential. We demonstrate the displacement and separation of DNA with a throughput that is one to five orders of magnitude greater than other microfluidic techniques. Using a device with a small footprint (23 mm × 0.5 mm), and with feature sizes in the micrometre range, it is considerably easier to fabricate than parallelized nano-array-based approaches. We show the separation of 48.5 kbp and 166 kbp DNA strands achieving a significantly improved throughput of 760 ng/h, compared to previous work and the separation of low concentrations of 48.5 kbp DNA molecules from a massive background of sub 10 kbp fragments. We show that the extension of DNA molecules at high flow velocities, generally believed to make the length-based separation of long DNA difficult, does not place the ultimate limitation on our method. Instead, we explore the effects of polymer rotations and intermolecular interactions at extremely high DNA concentrations and postulate that these may have both negative and positive influences on the separation depending on the detailed experimental conditions

Ambulanssjuksköterskors erfarenheter av hot och våld : En intervjustudie

Hot och våld är vanligt förekommande inom ambulanssjukvården och har ökat det senaste decenniet. Ambulanssjuksköterskor möter människor i alla åldrar och i varierande miljöer i sitt arbete. Vid situationer där hot och/eller våld förekommer kan ambulanssjuksköterskorna riskera att tappa kontrollen över situationen. Detta kan resultera i bristfällig undersökning då ambulanssjuksköterskorna tvingas att ta avsteg från rutinundersökning exempelvis mätning av vitalparametrar. Forskning påvisar också att hot och våld kan ha negativa konsekvenser på ambulanssjuksköterskans välbefinnande och ge ökad stress. Syftet med studien var att beskriva ambulanssjuksköterskors erfarenheter av hot och våld. Studien var en kvalitativ intervjustudie med induktiv ansats då innehållet i intervjuerna använts som utgångspunkt. Droger, alkohol och andra bakomliggande sjukdomar är bidragande orsaker till varför hot och våld uppstår mot ambulanssjuksköterskor. Resultatet beskrev att ambulanssjuksköterskans tidigare erfarenheter var av stor vikt då det kunde vara avgörande för hur de hanterar dessa situationer och hur de fortlöpte. Erfarenheterna påverkade även hur ambulanssjuksköterskorna förberedde sig för att undvika att hamna i allvarliga situationer. Ambulanssjuksköterskor upplever en rädsla inför att vårda patienter där hot eller våld kan förekomma. Detta kan försvåra arbetet då ambulanssjuksköterskorna i värsta fall frångår rutinerna och riskerar patientsäkerheten. I resultatdiskussionen uppmärksammas om ambulanssjuksköterskor har tillräckligt med utbildning för att hantera hot och våldssituationer. Ökade kunskaper och ökad förståelse inom hot och våld kan bidra till att ambulanssjuksköterskorna får en ökad trygghet i sitt dagliga arbete

Reklam, mat & ko(n)sten att synas : En kvalitativ studie av fyra reklamfilmer från Coop och Lidl

Almost every commercial in television nowadays aim to sell a product or service. This researchpresents two big actors in the grocery chain and their respective commercials. The two actors thatare presented in this research are Lidl and Coop. Both Lidl and Coop are among the largest grocerychains in Sweden. By examine two commercials from each company we aim to find how theircommercials are structured. It’s also interesting to search how they work with commercials alongtheir business idea. What makes this research relevant is that it has been relatively few studies onthis case. The theory used in this study is mainly the semiotic approach but also the narrative andthe rhetoric theories are used. The result and discussion section reveals each companies commercialstructure and how they integrate their business idea. The discussion also reveals similarities anddifferences between Lidl and Coop. Finally, the conclusions of this study are discussed