Upsala journal of medical sciences最新文献

This paper summarizes the efforts to develop novel biomarkers for diagnosis and screening of the three main gynecological cancers, cervical, endometrial, and ovarian cancer, with an emphasis on research performed during the last 20 years in Uppsala. A cervical cancer screening program has existed in Sweden since 1966 using cytology as the primary test. Over the last two decades, research has provided the scientific base for a transition to self-sampling to improve convenience of the woman and achieve higher population coverage, and use of human papillomavirus as the primary test. Also, efficient prophylactic vaccines and more efficient treatment strategies of women with cervical dysplasia have been introduced. Together, these medical tools have the potential to eradicate cervical cancer by 2120, as envisaged by WHO. By contrast, efficient biomarkers for endometrial and ovarian cancer are still lacking. Through the use of high-throughput proteomics, we have identified novel plasma protein biomarkers to be used in the diagnosis of women with adnexal ovarian mass upon transvaginal ultrasound, and possibly also for early detection in population screening. Similarly, novel biomarkers for the diagnosis of endometrial cancer are being evaluated. To establish a population-based screening program requires careful cost-benefit analyses. One alternative would be to broaden the focus of the current cervical cancer screening program to include also the novel biomarkers for ovarian and endometrial cancer, and thereby achieve screening for all three gynecological cancers. A program that screens for all three diseases could increase motivation to participate and thereby population coverage.

Background: Oncolytic viruses are promising tools for immune stimulatory gene therapy of cancer, but their clinical effect on solid tumors have so far been limited. Transduction of the target tumor cells is limited by both extracellular matrix that blocks viral spread within the solid tumor tissue and electrostatic forces that inhibit virus from binding its entry receptor on the cell surface. The enzymes hyaluronidase and collagenase and the polycations diethylaminoethyl (DEAE)-dextran, branched Polyethylenimine (PEI) and protamine sulfate have previously shown potential to improve gene transfer in different forms of viral gene therapy, since they may help the virus to overcome these barriers. In this study, we compared the transduction-enhancing potential of these substances when used as vehicles for adenoviral transduction in solid tumor tissue.

Methods: Subcutaneous tumors of pancreatic ductal adenocarcinoma were established in mice and treated with a mix of adenoviral vector Adf35(GFP-Luc) and either one of the selected vehicles. Transduction efficacy was determined by quantification of the viral transgene expression level using live imaging.

Results: Addition of hyaluronidase tripled the transgene expression of Adf35(GFP-Luc) when compared to virus alone. No such positive effect was seen for the other tested vehicles.

Conclusions: Out of the tested candidates, hyaluronidase showed the best potential to facilitate viral spread in tumor tissue and transduction of tumor cells. Therefore, hyaluronidase may be used as vehicle to improve clinical efficacy of oncolytic virotherapies.

Background: Growth differentiation factor 15 (GDF-15) is a robust prognostic biomarker in patients with cardiovascular (CV) disease, and a better understanding of its clinical determinants is desirable. We aimed to study the associations between GDF-15 levels and traditional CV risk factors, indicators of atherosclerotic burden, and cardiac geometry and dysfunction in outpatients with peripheral arterial disease (PAD).

Methods: An explorative cross-sectional study (Study of Atherosclerosis in Vastmanland, Västerås, Sweden) included 439 outpatients with carotid or lower extremity PAD. The mean age was 70 years (standard deviation [SD] 7), and 59% of the patients were men. Plasma levels of GDF-15 were obtained along with potential determinants, including medical history, biochemical data, echocardiographic measures of cardiac geometry and function, ankle-brachial index (ABI), and carotid ultrasonographic data on intima-media thickness (IMT) and occurrence of carotid stenosis. The relations between GDF-15 concentrations (transformed with the natural logarithm) and the different determinants were evaluated using uni- and multivariable linear regression models. All pre-specified variables were included in the multivariable models.

Results: The multivariable analysis identified independent relations of GDF-15 with several of the included variables (adjusted R ² = 0.48). Diabetes (beta coefficient [β] of 0.37, 95% confidence interval [95% CI] 0.25 to 0.50), low-density lipoprotein (LDL) cholesterol (β = -0.22, 95% confidence interval [CI]: -0.34 to -0.09), and physical activity (β = -0.16, 95% CI: -0.25 to -0.06) had the strongest associations. In contrast, no significant independent associations with GDF-15 level were observed for cardiac geometry and function, ABI, IMT, or carotid stenosis.

Conclusions: Circulating GDF-15 is more strongly associated with traditional CV risk factors, especially diabetes, LDL cholesterol, and physical activity than with specific indicators of atherosclerotic burden or cardiac dysfunction. To better understand the pathophysiological role of GDF-15 and its link to clinical outcomes in patients with PAD, future studies should focus on the metabolic processes involved in atherosclerotic disease.

In the 1980s, my research career begun with microbial DNA diagnostics at Orion Pharmaceutica in Helsinki, Finland, where I was part of an innovative team that developed novel methods based on the polymerase chain reaction (PCR) and the biotin-avidin interaction. One of our key achievements during this time was the invention of the solid-phase minisequencing method for genotyping single nucleotide polymorphisms (SNPs). In the 1990s, I shifted focus to human genetics, investigating mutations of the 'Finnish disease heritage'. During this period, I also developed quantitative methods using PCR and minisequencing of mitochondrial mutations and for forensic analyses. In the late 1990s and early 2000s, microarray-based SNP genotyping became a major topic for my research, first in Helsinki and later with my research group at Uppsala University in Sweden. By the mid-2000s, I began collaborating with leading clinicians on genetics of autoimmune disease, specifically systemic lupus erythematosus and later worked on the classification and clinical outcome of pediatric acute lymphoblastic leukemia, when large-scale genomics and epigenomics emerged. These collaborations, which focused on integrating genomics into clinical practice, lasted almost two decades until I retired from research in 2022. In parallel with my research activities, I led the SNP/DNA Technology Platform in the Wallenberg Consortium North program from 2001 to 2006. I continued as Director of the SNP&SEQ Technology Platform, which expanded rapidly during the 2010s, and became part of Science for Life Laboratory in 2013. Today (in 2024), the SNP&SEQ Technology Platform is one of the largest units of the Swedish National Genomics Infrastructure hosted by SciLifeLab. The present article provides a personal perspective on nearly four decades of research, highlighting projects and methods I found particularly exciting or important.

Background: Higher circulating levels of tumor necrosis factor (TNF) alpha receptors 1 (TNFR1) and 2 (TNFR2) are associated with increased long-term mortality and impaired kidney function.

Aim: To study associations between levels of TNFR1 and TNFR2 and all-cause mortality as well as estimated glomerular filtration rate (eGFR) decline.

Population and methods: Patients with chronic kidney disease (CKD) stages 3-5 in the Salford Kidney Study were included. Associations between one standard deviation increase in plasma TNFR1 and TNFR2 and mortality were estimated by Cox regression models with hazard ratios (HRs) and 95% confidence intervals adjusted for age, sex, eGFR based on creatinine and cystatin C, urine-protein, C-reactive protin, cardiovascular comorbidity, smoking habits, and diabetes. Differences in eGFR decline in relation to plasma TNFR1 and TNFR2 were estimated by both linear and logistic regression models, with regression coefficients and odds ratios (ORs).

Results: Univariate models showed significant associations between TNFR1 (n = 985) and TNFR2 (n = 988) and all-cause mortality based on 7424 person-years at risk, but in the fully adjusted models with continuous variables significant only for TNFR2 HR 1.17 (1.03-1.34), but with a borderline value for TNFR1 HR 1.15 (1.00-1.31). For rapid decliners, that is, eGFR decline in highest TNFR-receptor quartile versus quartiles 1-3, the decline was 1.60% per month (interval 0.78-10.99). For eGFR decline in continuous models, the fully adjusted ORs were for TNFR1 1.29 (0.92-1.81) and for TNFR2 1.33 (0.90-1.98).

Conclusions: TNFR2 was associated with mortality, but TNFR1 was not, although showing a borderline value. Neither TNFR1 nor TNFR2 predicted decline in kidney function. TNFR1 and TNFR2 portray interesting aspects in patients with CKD, but the clinical utility seems limited.

Objective: This study aims to assess the external validity of the Alcohol Use Disorders Identification Test (AUDIT) in Swedish prenatal care as an indicator for alcohol-addiction disorders, and to characterize women with mismatched information in healthcare registers.

Design: This study was designed as a National register-based study.

Setting: Sweden.

Participants: The study sample included 739,735 pregnancies over the period 2014-2020.

Methods: Prospectively collected prenatal AUDIT screening in the Swedish Pregnancy register was linked to national health databases through individual identification number. The AUDIT score was dichotomized into < 6 points (low-risk use) and ≥ 6 points (hazardous use). Alcohol addiction disorders were defined by a diagnostic code in The Swedish National Patient Register or drugs dispensed for alcohol dependence in the Swedish Prescribed Drug Register.

Primary outcome measures: The diagnostic properties of AUDIT were assessed based on sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), negative likelihood ratio (LR-), and accuracy (proportion of true positive and true negative) for an AUDIT score of ≥ 6 points for alcohol disorders. Women with mismatched information in the register were characterized and assessed by multinominal logistic regression, using women with matched information in the registers for reference.

Results: An alcohol-related disorder was recorded in 3.1%, while 25,770 (3.5%) had an AUDIT point ≥ 6. The diagnostic accuracy of the AUDIT ≥ 6 points for detection of an alcohol related disorder during a year prior to pregnancy was 95.7% (95% confidence interval [CI]: 95.7, 95.8), with a positive LR of 8.03 (95% CI: 7.5, 8.6). The sensitivity for detecting a pre-pregnancy alcohol related disorder was 33.0% (95% CI: 30.9, 35.1). Being young, nulliparous, of low education, and of Swedish origin increased the likelihood of being misclassified with the AUDIT. Prior psychiatric care was associated with false negatives, especially for women with neuropsychiatric disorders (odds ratio [OR]: 10.39, 95% CI: 9.89, 10.90).

Conclusions: The accuracy of AUDIT in screening for alcohol disorders at a population-based level was high, but only identified one third of women with alcohol-related disorders when using a cut-off of six points criterion.

Background: Transcatheter aortic valve implantation (TAVI) has shown similar or improved clinical outcomes compared with surgical aortic valve replacement (SAVR) in patients with symptomatic severe aortic stenosis at low risk for surgical mortality. This cost-utility analysis compared TAVI with SAPIEN 3 versus SAVR in symptomatic severe aortic stenosis patients at low risk of surgical mortality from the perspective of the Swedish healthcare system.

Methods: A published, two-stage, Markov-based cost-utility model that captured clinical outcomes from the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated according to Recommended Therapies (SWEDEHEART) registry (2018-2020) was adapted from the perspective of the Swedish healthcare system using local general population mortality, utility and costs data. The model had a lifetime horizon. Model outputs included changes in direct healthcare costs and health-related quality of life from using TAVI as compared with SAVR.

Results: TAVI with SAPIEN 3 resulted in lifetime costs per patient of 940,541 Swedish krona (SEK) and lifetime quality-adjusted life years (QALYs) per patient of 7.16, whilst SAVR resulted in lifetime costs and QALYs per patient of 821,380 SEK and 6.81 QALYs, respectively. Compared with SAVR, TAVI offered an incremental improvement of +0.35 QALY per patient at an increased cost of +119,161 SEK per patient over a lifetime horizon, resulting in an incremental cost-effectiveness ratio of 343,918 SEK per QALY gained.

Conclusion: TAVI with SAPIEN 3 is a cost-effective option versus SAVR for patients with symptomatic severe aortic stenosis at low risk for surgical mortality treated in the Swedish healthcare setting. These findings may inform policy decisions in Sweden for the management of this patient group.

Background: Open-angle glaucoma (OAG) is a leading cause of irreversible blindness. There are no prospective studies on the risk of developing blindness in both eyes in individuals with definite OAG.

Methods: A total of 354 patients with newly diagnosed OAG, who had participated in four studies conducted at the Eye Department in Tierp, Sweden, from 1979 to 2006, were included in the investigation. Using the World Health Organization's criteria for blindness, medical records, glaucoma case records, and visual fields were reviewed to identify patients who developed bilateral blindness. Incidence proportions and incidence rates were estimated. To assess potential risk factors for blindness, standardised morbidity ratios (SMRs) were calculated. The effects of age and sex were also analysed using Cox proportional hazard models.

Results: By the end of the study in August 2023, 33 cases of blindness caused by OAG had been found, corresponding to an incidence proportion of 9.3% (95% confidence interval [CI]: 6.5-12.8%). Within the first 20 years, 29 cases were detected, yielding a proportion of 8.2% (95% CI: 5.5-11.6%). The incidence rate was estimated to be 8.6 per 1,000 person-years (95% CI: 5.9-12.6 per 1,000 person-years). Glaucoma-related blindness was associated with male sex (SMR 2.33; 95% CI: 1.13-4.80). The hazard ratio was doubled for every 5 year of increasing age (2.21; 95% CI: 1.60-3.05).

Conclusion: In this study of blindness in newly diagnosed OAG in a Swedish population, approximately one in 10 patients progressed to bilateral blindness caused by the disease. Old age and male sex were identified as significant risk factors.

Background: Tenecteplase is increasingly used off-label as an alternative to alteplase for ischemic stroke thrombolysis. Our aim was to evaluate the safety of tenecteplase versus alteplase in comprehensive real-world data.

Methods: We compared the outcomes for adult patients with acute ischemic stroke treated with alteplase or tenecteplase, registered in the Swedish Stroke Register between January 1, 2018 and December 31, 2020. The primary outcome was symptomatic intracerebral hemorrhage or death during hospital stay. Secondary outcomes were death within 90 days, modified Rankin Scale at 90 days, and mean door-to-needle time (DNT).

Results: There were no significant differences in age or risk factors between 6,560 patients (45% women, mean age 74) treated with alteplase and 888 patients (43% women, mean age 74) treated with tenecteplase, although tenecteplase was more commonly used in non-university hospitals, hospitals with high use of thrombolysis, and in wake-up strokes. Tenecteplase was not non-inferior compared to alteplase in terms of symptomatic intracerebral hemorrhage or death during hospital stay (13.2% vs. 10.7%, absolute risk difference [95% confidence interval, CI] 2.5% [0.1 to 4.9%], adjusted odds ratio 1.44 [1.07-1.94]). There were no significant differences in functional outcome or death at 90 days, but tenecteplase was associated with decreased DNT (mean difference 9 min).

Conclusion: Tenecteplase was not non-inferior in safety outcome, although associated with decreased DNT. As accumulating randomized controlled studies support the non-inferiority of tenecteplase regarding functional outcome, it is important to keep scrutinizing the safety outcomes.