Long-term survival and survivorship in non-Hodgkin lymphoma patients in Sweden

Non-Hodgkin lymphoma (NHL) is one of the top ten most common cancer types in Sweden. Although sometimes referred to as one disease, NHL is truly an umbrella term representing a heterogeneous group of diseases with varying clinical course and prognosis. The main data source for all four studies included in this thesis is the Swedish lymphoma register (SLR). This national quality register provides population-based data, detailed clinical information and the possibility to distinguish between different morphological subtypes of NHL. In Study I we provide a systematic presentation of temporal trends in absolute numbers of prevalent patients by NHL subtypes, linking them to trends in incidence, survival and mortality. Poisson regression was used to test for temporal trends. We found that an increasing incidence and improved survival have led to an increase in the prevalence of NHL overall and for almost all investigated subtypes between 2000 and 2016. This increase was most notable for diffuse large B-cell lymphomas (DLBCL) among aggressive subtypes and marginal zone lymphomas among indolent subtypes. The prevalence provides a measure of burden of disease, useful for health care planning and to optimize resource allocation. The prevalence also represents the number of survivors in the population, at risk for relapses and psychological and physiological side effects of their lymphoma or treatment. The increase in number of prevalent NHL patients underscores the need to develop and evaluate alternative follow-up schemes of lymphoma survivors since especially patients diagnosed with indolent lymphoma subtypes are followed in the clinic for many years. The most common subtype of NHL, DLBCL is the focus in study II-IV. In recent years, the addition of rituximab to the standard combination chemotherapy has improved outcomes in patients with DLBCL. Nevertheless, every fourth patient treated curatively is expected to experience progressive disease or relapse. Study II aimed to quantify trends and remaining loss in life expectancy due to DLBCL in a population-based cohort. Loss in life expectancy was predicted using flexible parametric models from diagnosis and among two-year survivors, by age, sex and age-adjusted international prognostic index (aaIPI). The number of life-years lost decreased over the study period 2000-2013 in all patient groups. However, especially younger patients (≤60 years) with aaIPI≥2 were still estimated to lose many life years in 2013. Among two-year survivors, the loss in life-expectancy was reduced to two years or less by the end of the study period, regardless of age, sex and aaIPI. By using novel measures, we illustrated the improvement of DLBCL survival in a population-based context and over the entire life-span. The standard chemotherapy for curative treatment of DLBCL contains the cardiotoxic anthracycline doxorubicin. An increased rate of heart failure is well documented following this treatment, whereas incidence and outcome of other cardiac complications, e.g. myocardial infarction, are less well studied. In Study III we assessed the incidence, characteristics and outcome of acute myocardial infarctions (AMI) in curatively treated patients with DLBCL. Patients were matched to lymphoma-free comparators and the rate of AMI was estimated using flexible parametric survival models incorporating repeated events. Overall, DLBCL patients had a 33% excess rate of AMI compared to the general population. However, the excess rate was most pronounced during the first year after diagnosis and diminished after 2 years. The strongest risk factors for AMI were advanced age, male sex and pre-existing comorbidity. There was no difference in AMI characteristics, extent of treatment or 30-day survival following hospitalization for AMI between DLBCL patients and comparators. The increased risk of AMI especially during the first 2 years and among elderly patients calls for improved cardiac monitoring. In Study IV we estimated real-world probabilities for lasting remission by clinical disease characteristics using a multi-state model approach. DLBCL patients who achieved remission after primary treatment were followed for repeated relapses and death. Flexible parametric models were used to model transition rates between disease stages accounting for competing events at each transition. At 2 years after end of primary treatment, 81% of the patients remained in remission, 13% had relapsed and 6 % of patients had died in first remission. The probability of remaining in remission for at least 2 years was reduced by 24 percentage units for patients with international prognostic index, IPI 4-5 compared to patients with IPI 0-1. On average, these patients lost 4.4 months of being in remission the first 2 years. Only 43% of relapsing patients achieved a second remission and half of them (51%) relapsed again - reflecting the difficulties in treating relapsing patients

Season of birth, childhood asthma and allergy in a nationwide cohort : mediation through lower respiratory infections

Background: Previous studies have suggested an association between season of birth and risk of childhood asthma and allergic disease. The association may be modified by birth year and region, or mediated by respiratory tract infections. Objective: We aimed to estimate the association between season of birth and risk of childhood asthma/wheeze or allergic rhinoconjunctivitis in a population-based setting, and the mediating effect of lower respiratory infections. Methods: Two population-based cohorts were identified from the nationwide Swedish Medical Birth, Patient and Prescribed Drug Registers. The association between birth month/season and asthma/wheeze incidence was analysed using Cox proportional regression in the younger cohort born 2005-2010 (n = 582 494) and asthma/allergic rhinoconjunctivitis prevalence during the 7th year of life using log-binomial models in the older cohort born 2001-2004 (n = 367 583). Interactions were formally tested. Mediation analyses to address the effect of lower respiratory infections were performed in the older cohort using the R package "medflex." Results: Children born during fall and winter had an increased risk of asthma/wheeze after 2 years of age in the younger cohort: hazard ratio 1.24 (95% confidence interval, CI 1.17, 1.33) for winter and risk of prevalent asthma during their 7th year of life in the older cohort; prevalence ratio (PR) 1.12 (95% CI 1.08, 1.16) for winter. These estimates were partly mediated by lower respiratory infections; the indirect effect for winter compared with summer was PR 1.03 (95% CI 1.03, 1.04). The association was similar for allergic rhinoconjunctivitis in the 7th year of life, but not mediated by respiratory infections.Conclusion: We found that the association between season of birth and risk of childhood asthma/wheeze, but not allergic rhinoconjunctivitis, is partly mediated through lower respiratory infections. Clinical relevance: This has important implications for patient care, such as asthma management programmes to notify timing of seasonality for viral respiratory tract infections.Swedish Research Council for Health, Working Life and Welfare, Grant/Award Number: 2015-00289Swedish Research Council, Grant/Award Number: 2018-02640 and 340-2013-5867Swedish HeartLung Foundation, Grant/Award Number: 20150440 and 20180512Stockholm County CouncilKarolinska InstitutetAccepte

Improvement of personality functioning among people treated within personality disorder mental health services. A longitudinal, observational study

Objective: Evidence-based personality disorder (PD) treatments are dominated by interventions targeting Borderline PD, although clinical populations characteristically include different PD features and severity. Personality functioning is a new concept intended to capture common features across PDs. This study aimed to investigate longitudinal improvement of personality functioning in a clinical sample assigned to PD treatment. Method: An observational, large, longitudinal study of patients in PD treatments on specialist mental health service levels (N = 1,051). DSM-5 PDs were systematically assessed on referral. Personality functioning was repeatedly assessed (LPFS-BF-2.0), supplemented by symptom distress (anxiety: PHQ-GAD-7, depression: PHQ-9), and social/occupational activity (WSAS, work/study activity). Statistics were linear mixed models. Results: Thirty per cent had personality difficulties below PD threshold. Among PDs, 31% had Borderline (BPD), 39% Avoidant (AvPD), 15% not otherwise specified, 15% other PDs, and 24% > one PD. More severe initial LPFS-BF was associated with younger age, presence of PD and increasing number of total PD criteria. Across PD conditions, LPFS-BF, PHQ-9 and GAD-7 improved significantly (overall effect size 0.9). Mean duration of PD treatment was 15 (SD 9) months. Drop-out rates were low (12%). LPFS-BF improvement-rates were higher for BPD. Younger age was moderately associated with slower PHQ-9 improvement. Work/study activity was initially poor, poorer levels associated with AvPD and younger age, and improvement was non-significant across PD conditions. AvPD was associated with slower WSAS improvement-rates. Conclusion: Personality functioning improved across PD conditions. The results highlight BPD improvements. The study points to challenges concerning AvPD treatment, poor occupational activity and age-related differences

STUDENTERS STRATEGIER FÖR EN BÄTTRE HÄLSA Strategier som studenter på Sahlgrenska Akademin använder sig av för att bibehålla aktivitetsbalans i vardagen

Bakgrund: Psykisk ohälsa har under de senaste åren ökat bland studenter på Sahlgrenska Akademin. Över hälften av studenterna upplever psykisk ohälsa och många överväger att avbryta sina studier på grund av bland annat stress. Inom arbetsterapi anses aktivitetsbalans vara en viktig del för att hälsa ska kunna uppnås. Genom aktivitetsbalans med rätt mängd av olika aktiviteter kan personer uppnå välmående, tillfredsställelse och hälsa. Strategier påverkar kunskap och lärande på ett positivt sätt och kan bidra till att aktivitetsbalans bibehålls under studietiden. Idag finns omfattande kunskap kring sambandet mellan aktivitetsbalans och hälsa. Dock finns ett kunskapsgap kring vilka strategier som studenterna på Sahlgrenska Akademin använder sig av för att bibehålla aktivitetsbalans i vardagen och därmed uppleva hälsa. Syfte: Syftet med studien var att beskriva strategier som studenter på Sahlgrenska Akademin använder sig av för att bibehålla aktivitetsbalans i vardagen. Metod: Sex semistrukturerade intervjuer genomfördes med studenter på Sahlgrenska Akademin, vilka hade studerat i minst ett år och använde sig utav strategier för att bibehålla aktivitetsbalans. Rekrytering av deltagare skedde genom informationsblad samt snöbollsmetoden. Intervjuerna har analyserats genom kvalitativ innehållsanalys enligt Graneheim och Lundman. Resultat: Resultatet utgjordes av sex kategorier: Fysisk aktivitet, Att ha en struktur, Social Gemenskap, Hitta sin lärostil, Meningsfulla aktiviteter och Acceptera sig själv. Av resultatet framkom att strategierna bland annat bidrog till allmänt bättre mående, att sömnen förbättrades och att strategierna även motverkade stress. Konklusion: Strategier i form av Fysisk aktivitet, Att ha en struktur, Social gemenskap, Hitta sin lärostil, Meningsfulla aktiviteter och Acceptera sig själv har visat sig vara till stor hjälp för deltagarna för att kunna bibehålla aktivitetsbalans i vardagen. Strategierna upplevs av deltagarna ha en god effekt på studierna samt på hälsan. Då aktivitetsbalans är kopplat till hälsa är det därmed till stor vikt att det finns utrymme för att kunna använda sig av strategier i samband med studier

Cryopreservation of Oocytes : Comparison between the Cryoloop and the Cryopette vitrification techniques

Crypreservation of oocytes is recently being considered to be a valid choice in infertility treatments.Low survival and fertilization rates due to inefficient slow freeze protocols have been the outcome ofmany previous studies done in the field. However, introduction of the vitrification technique and itsapplication in reproductive medicine and to some extent new improved slow freeze protocols haveshown that oocytes can be cryopreserved with successful outcome. In this project the survival rate of oocytes after vitrification with MediCult Vitrification andWarming Media has been studied. Also, a comparison of the carriers Cryoloop (an open system) andCryopette (a closed system) has been performed. A total of 43 oocytes were vitrified and warmed according to MediCult's protocol, of which 21oocytes with Cryoloop and 22 with Cryopette. The cells were post-thaw incubated in a physiologicalenvironment for 24h. During that time the morphology and viability were observed and noted after 2h,over night and after 24h. No significant difference in survival rates of the oocytes' was observed usingthe two carriers, and the total survival rate of the oocytes was 83.7%. This indicates thatcryopreservation of oocytes is a valid choice in fertility treatments and that the new product Cryopettecan be used clinically with just as good results as the well established Cryoloop technique. This merits further studies on the applicability of vitrification on oocytes and the Cryopette technique

Evaluation and implementation of quality control parameters for genome-wide DNA methylome sequencing

Epigenomics is the study of modifications to the genetic material without changes to the DNA sequence, one such modification is methylation of nucleotides. DNA methylation is associated with gene regulation and is studied in a variety of fields such as cancer and ageing. Quality control is essential when designing research studies to ensure that the end result is not affected by poor quality data. In this study, the aim was to define robust quality parameters for whole methylome sequencing for Illumina next generation sequencing data. Three different library preparation protocols, all designed for methylation analysis, has been compared: Accel-NGS Methyl-Seq DNA library, NEB Next Enzymatic Methyl-seq and SPlinted Ligation Adapter Tagging. All samples were sequenced on the Illumina NovaSeq 6000 with paired-end 150 bp. An evaluation of alignment software was also included in the study. The nf-core methylseq pipeline version 1.6.1 was used to process all samples in the study. The pipeline was run multiple times with different settings depending on library type and software choice. Throughout the study, the parameters puc19, lambda and alignment rate showed consistency whereas overall methylation rate and coverage were affected by origin of sample material and study design. In conclusion, not all proposed quality parameters were suitable for general quality control since study design and origin of sample material have impact, but alignment rate and the controls puc19 and lambda shows great promise for general quality control. Future work to establish sample material specific thresholds for methylation rate is encouraged

Are opportunities and threats enough? A development of the labels of strategic issues

This study joins the scholarly discussion that uses strategy in media management and provides a developed framework of strategic issues. This paper assists organisations in overcoming uncertainty by helping them construct issues and not impose the opportunity or threat labels on ill-defined issues. Based on a qualitative case study of two newspapers that represent an industry in disruption, this paper extends the existing conceptual framework on strategic issues by providing an additional strategic issue label, amorphous issues, that captures the uncertainties organisation members face during periods of disruption. Moreover, this paper also illustrates how the construction of issues can change over time. This emphasises the dynamic nature of strategic issues construction, which more closely aligns with the disruptive environment in which many contemporary organisations operate