Treatment of coagulopathy in patients with critical COVID-19

Introduction: Thromboembolic complications affect a large proportion of patients with critical COVID-19, and it may be associated with an increased risk of death. It has been hypothesized that both the virus of SARS-CoV-2 itself and the inflammation caused by the infection puts patients in a pro-coagulative state. To reduce the risk of thromboembolism, lowmolecular weight heparins are recommended as thromboprophylaxis for all patients in intensive care, including patients with critical COVID-19. The overall aim of this thesis was to investigate treatment of coagulopathy in patients with critical COVID-19. Specifically, studies I and II aimed to investigate the association with outcomes by different dosing of lowmolecular- weight heparins, study III aimed to study the outcome depending on the dosage of glucocorticoids, and study IV explored outcomes associated with the monitored effect of lowmolecular- weight heparins by anti-Factor Xa measurements. The overall goal was to find ways to mitigate the risk of death and thromboembolism in patients with critical COVID-19 without increasing their risk of bleeding. Methods: Studies I, II, and IV were retrospective observational cohort studies, whereas study III was a post hoc analysis of an international, randomized, blinded trial. In all our studies, we included adult patients with critical COVID-19, defined as patients with polymerase chain reaction positive severe acute respiratory syndrome coronavirus 2, requiring intensive care due to respiratory failure. Patients were excluded if they already had the outcomes of thromboembolism or major bleeding at ICU admission. The four studies investigated patients during different time periods: studies I and II during the first wave, study III during the second wave, and study IV during both the first and second waves. The exposures in the first two studies were different doses of low-molecular-weight heparin: a low, intermediate, and high dose in study I, and an intermediate and high dose in study II. In study III, 12 versus 6 mg dexamethasone daily was investigated and in study IV, the activity of low-molecular-weight heparin by anti-Factor Xa was the exposure. Death, thromboembolism, and bleeding were the outcomes in all studies. To analyze the primary outcome, Cox regression was used in studies I, II and III, and logistic regression was used in studies III and IV. Multivariable models were used to adjust for pre-defined baseline variables with the potential to affect the outcome in studies I and II, for stratifying variables in study III, and for one potential confounder and interaction in study IV. Results: In study I, high dose low-molecular-weight heparin was associated with a significant reduction of death at 28 days compared to low dose: adjusted hazard ratio 0.33 (95% CI 0.13 to 0.87). There was also a lower incidence of thromboembolism for patients treated with high (2.7%) versus intermediate (18.8%) and low dose low-molecular-weight heparin (17.9%) (p = 0.04) but no difference in the risk of bleeding (p = 0.16). When focusing on intermediate vs high dose low-molecular-weight heparin in study II, we found no differences in the risk of death at 90 days, thromboembolism or bleeding at 28 days, with hazard ratios of 0.74 (95% CI 0.36 to 1.53), 0.93 (95% CI 0.37 to 2.29), and 0.84 (95% CI 0.28 to 2.54), respectively. In study III, the incidence of the composite outcome death and thromboembolism during the ICU stay did not differ for patients randomized to 12 or 6 mg dexamethasone, odds ratio 0.93 (95% CI 0.58 to 1.49), nor were there any significant differences for the secondary outcomes of thromboembolism, major bleeding, or any bleeding complications. In study IV, when analyzing anti-Factor Xa as a continuous variable in a spline model, associations were found between (1) lower peak anti-Factor Xa values and increased risk for thromboembolism and (2) higher trough anti-Factor Xa values and an increased risk of death and bleeding. When cut-off values of peak were investigated, patients with any value below 0.3 kIU/L had an associated odds ratio of thromboembolism of 5.1 (95% CI 1.8 to 14.4) compared to patients no values below 0.3 kIU/L. Trough values above 0.3 kIU/L were associated with an odds ratio of bleeding of 1.9 (95% CI 1.1 to 3.3), and trough values above 0.5 kIU/L were associated with an odds ratio of 2.4 (95% CI 1.0 to 5.6) of major bleeding, compared to patients with no values above these levels. Conclusion: In the early days of the pandemic, we found that a high dose of low-molecularweight heparin for thromboprophylaxis was associated with lower mortality compared to low dose. The results also suggested a benefit with high dose compared to intermediate dose, but no such association was found when including more patients and comparing only thromboprophylaxis with intermediate vs high dose low-molecular-weight heparin. A daily dose of 12 or 6 mg of dexamethasone did not result in a significant decrease in the composite outcome of death and thromboembolism, thromboembolism, or bleeding. Anti-Factor Xa values may be useful to guide thromboprophylaxis in patients with critical COVID-1

Stockholms Nöjespir

This project introduces the typology of the Pleasure Pier to Stockholm. The Pier starts at Ropsten, an area in the center of the municipality´s extensive plans for The Royal Seaport (or Norra Djurgårdsstaden). The project is a study of the pier typology, how to translate an old idea to give it relevance to Stockholm today, how a structure can be integrated in the intense traffic node that Ropsten will become, and how Stockholm´s abundance of water can become more accessible without diminishing its value

Tissue biomarkers in prostate cancer

Prostate cancer (PC) is the most common male cancer in the western world. Better biomarkers are needed to support diagnosis, prediction of prognosis and treatment decision Radical prostatectomy (RP) specimens are routinely immersed in formalin overnight. Formalin may also be injected into the prostate for improved fixation. We report that formalin injection does not alter tissue volumes compared to conventional fixation. Formalin may affect epitopes for immunohistochemistry (IHC). Immunoreactivity was compared between fixation methods with no significant difference for the majority of 15 antibodies. We investigated the transcription factor pancreatic duodenal homeobox-1 (PDX-1) and heat shock proteins (HSP) 27, 60 and 70 as prognostic markers in PC. A tissue microarray (TMA) of 289 PCs was constructed and immunostained. HSP 27 and 60, but not HSP 70 and PDX-1 correlated with biochemical recurrence. In multivariate analysis including histopathological prognostic factors, only HSP 60 was an independent predictor of prognosis. PDX-1 was overexpressed in cancer vs. benign tissue but also in atrophy and high-grade prostatic intraepithelial neoplasia (PIN) vs. cancer. The role of GAD1 (glutamate decarboxylase 1) as prostate-specific biomarker was investigated. A TMA of benign and malignant tissues from prostate, rectum, lung and bladder was stained for GAD1, prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA, glutamate carboxypeptidase). Presence of GAD1 protein was validated by Western blot and real-Time PCR (RT-PCR). By IHC, the expression of GAD1 and PSA was stronger in prostatic tissues than in controls. PSMA was stronger in prostate cancer than in urothelial and rectal cancer but had lower specificity than GAD1 and PSA. The intra- and interobserver reproducibility of IHC evaluation in TMA were assessed. Intensity and extent of PDX-1 immunostains of 50 PCs were scored twice by 4 independent observers. Mean weighted kappa for intra- and interobserver agreement was 0.85 and 0.80 for intensity and 0.43 and 0.21 for extent with similar results for 2 pathologists and 2 non-pathologists. Thus, subjective assessment of intensity is highly reproducible while estimation of staining extent is less reliable. In conclusion, we find that TMA is a valuable tool for tissue-based biomarker research. We have attempted to optimize the procedures from tissue handling to evaluation. We also present HSP 27 and HSP 60 as potential predictors of prognosis in PC and GAD1 as a new prostate-specific biomarker