Effectiveness of mRNA booster vaccination against mild, moderate, and severe COVID-19 caused by the Omicron variant in a large, population-based, Norwegian cohort

Background Understanding how booster vaccination can prevent moderate and severe illness without hospitalization is crucial to evaluate the full advantage of mRNA boosters. Methods We followed 85 801 participants (aged 31–81 years) in 2 large population-based cohorts during the Omicron BA.1/2 wave. Information on home testing, PCR testing, and symptoms of coronavirus disease 2019 (COVID-19) was extracted from biweekly questionnaires covering the period 12 January 2022 to 7 April 2022. Vaccination status and data on previous SARS-CoV-2 infection were obtained from national registries. Cox regression was used to estimate the effectiveness of booster vaccination compared to receipt of 2-dose primary series >130 days previously. Results The effectiveness of booster vaccination increased with increasing severity of COVID-19 and decreased with time since booster vaccination. The effectiveness against severe COVID-19 was reduced from 80.9% shortly after booster vaccination to 63.4% in the period >90 days after vaccination. There was hardly any effect against mild COVID-19. The effectiveness tended to be lower among subjects aged ≥60 years than those aged <50 years. Conclusions This is the first population-based study to evaluate booster effectiveness against self-reported mild, moderate, and severe COVID-19. Our findings contribute valuable information on duration of protection and thus timing of additional booster vaccinations.publishedVersio

Homologous Recombination Deficiency Across Subtypes of Primary Breast Cancer

Purpose - Homologous recombination deficiency (HRD) is highly prevalent in triple-negative breast cancer (TNBC) and associated with response to PARP inhibition (PARPi). Here, we studied the prevalence of HRD in non-TNBC to assess the potential for PARPi in a wider group of patients with breast cancer. Methods - HRD status was established using targeted gene panel sequencing (360 genes) and BRCA1 methylation analysis of pretreatment biopsies from 201 patients with primary breast cancer in the phase II PETREMAC trial (ClinicalTrials.gov identifier: NCT02624973). HRD was defined as mutations in BRCA1, BRCA2, BRIP1, BARD1, or PALB2 and/or promoter methylation of BRCA1 (strict definition; HRD-S). In secondary analyses, a wider definition (HRD-W) was used, examining mutations in 20 additional genes. Furthermore, tumor BRCAness (multiplex ligation-dependent probe amplification), PAM50 subtyping, RAD51 nuclear foci to test functional HRD, tumor-infiltrating lymphocyte (TIL), and PD-L1 analyses were performed. Results - HRD-S was present in 5% of non-TNBC cases (n = 9 of 169), contrasting 47% of the TNBC tumors (n = 15 of 32). HRD-W was observed in 23% of non-TNBC (n = 39 of 169) and 59% of TNBC cases (n = 19 of 32). Of 58 non-TNBC and 30 TNBC biopsies examined for RAD51 foci, 4 of 4 (100%) non-TNBC and 13 of 14 (93%) TNBC cases classified as HRD-S had RAD51 low scores. In contrast, 4 of 17 (24%) non-TNBC and 15 of 19 (79%) TNBC biopsies classified as HRD-W exhibited RAD51 low scores. Of nine non-TNBC tumors with HRD-S status, only one had a basal-like PAM50 signature. There was a high concordance between HRD-S and either BRCAness, high TIL density, or high PD-L1 expression (each P Conclusion - The prevalence of HRD in non-TNBC suggests that therapy targeting HRD should be evaluated in a wider breast cancer patient population. Strict HRD criteria should be implemented to increase diagnostic precision with respect to functional HRD

Cancer-related venous thromboembolism: epidemiology and risk factors

The association between cancer and venous thromboembolism (VTE) was described already in the 19th century and cancer has later been acknowledged as one of the most important risk factors for VTE. Population-based studies on the subject with information about confounders and validated endpoints are lacking. The first aim of this thesis was to estimate the frequency of VTE among cancer patients in a population-based cohort study and assess the risk among cancer patients compared to a cancer-free reference population. Secondly, we wanted to investigate whether the level of leukocytes and platelets at inclusion influenced the future risk of VTE in cancer patients and in those who remained cancer-free. The fourth survey of the Tromsø study (Tromsø IV) was applied in all four papers of this thesis. The Tromsø Study is a prospective study of adult inhabitants of Tromsø. In Tromsø IV (1994-95), information from more than 27 000 subjects were collected by physical examination, self-administrated questionnaires and blood tests, and VTE events were registered throughout 2010. Information about cancer was provided by the Cancer Registry of Norway. In paper II, the Tromsø IV cohort was merged with two additional Scandinavian cohorts (i.e. HUNTII and DCH) and 137 000 subjects were included in the study. VTE occurred among 3-5 % of the cancer patients. Malignancy accounted for 20-25 % of the VTE events in the population, and the proportion was highest among middle-aged where cancer explained almost 30 % of the events. Patients with malignancy exhibited an overall 5-fold increased risk of VTE. The risk was highest during the initial 6 months after diagnosis (i.e. 17-fold increased) and declined thereafter. Patients with certain cancers, such as pancreatic-, lung- and brain cancers, had a particularly high risk of VTE. However, most cancers exhibited a high risk during the initial 6 months after diagnosis with incidence rates ranging from 30-90 cases per 1000 person-years for all sites, except for breast- and prostate cancers which had substantially lower risks. Despite the strong association between high age and VTE in the general population, the risk of VTE was similar across age-categories within the first year after a cancer diagnosis. We found that WBC- and platelet count were associated with VTE in cancer patients. Baseline leukocyte- or platelet count above the 80th percentile provided doubled risk of VTE compared to the 40th percentile, and the combined effect of the parameters was synergistic. The association was confined to subjects diagnosed with cancer, and the results suggest that platelet- and white blood cell counts have impact on the risk of cancer-related VTE

Platelet Count Measured Prior to Cancer Development Is a Risk Factor for Future Symptomatic Venous Thromboembolism: The Tromsø Study

Background: Elevated platelet count is associated with risk of venous thromboembolism in cancer patients initiating chemotherapy. It is not known whether this risk by platelet count is causal or merely reflects the malignant disease. We investigated whether pre-cancer platelet count alone or together with high leukocyte count was associated with risk of venous thromboembolism in subjects who did and did not develop cancer during follow-up in a population-based cohort study. Methods: Platelet count and other baseline characteristics were measured in 25160 initially cancer-free subjects who participated in the Tromsø Study in 1994–1995. Incident cancer and symptomatic venous thromboembolism events were registered up to December 31st, 2009. Multivariable Cox regression models were used to calculate hazard ratio for venous thromboembolism across categories of platelet count (,40th, 40–80th, and .80th percentile) with 95% confidence interval. Results: During follow-up, 2082 subjects were diagnosed with cancer. Platelet count was measured on average 8.3 years before the cancer diagnosis. There were 129 venous thromboembolism events in the cancer cohort (13.5 per 1000 personyears) and 377 in the non-cancer cohort (1.2 per 1000 person-years). In cancer patients, pre-cancer platelet count above the 80th percentile ($2956109/L) was associated with a 2-fold higher risk of venous thromboembolism (Hazard ratio: 1.98, 95% confidence interval 1.21–3.23) compared to platelet count below the 40th percentile (,2356109/L). Concomitant high platelet and leukocyte counts showed a synergistic effect on the VTE risk. In cancer-free subjects, no association was found. Comment: In conclusion, pre-cancer platelet count was associated with risk of symptomatic venous thromboembolism in cancer patients, but not in cancer-free subjects. Our findings suggest that platelet count and platelet-leukocyte interactions may play a role in the pathogenesis of cancer-related venous thromboembolism

White blood cell count measured prior to cancer development is associated with future risk of venous thromboembolism - The Tromsø Study

Background: Elevated white blood cell (WBC) count is associated with risk of venous thromboembolism (VTE) in cancer patients initiating chemotherapy. It is not known whether the risk of VTE by WBC count in cancer patients is causal or merely a consequence of the malignant disease. To address this question, we studied the association between WBC count, measured prior to cancer development, and risk of VTE in subjects who did and did not develop cancer during follow-up in a prospective population-based study. Methods: Baseline characteristics, including WBC and neutrophil counts, were measured in 24304 initially cancerfree subjects who participated in the Tromsø Study in 1994-1995. Incident cancer diagnosis and VTE events were registered up to September 1, 2007. In the cancer cohort, WBC and neutrophil counts were measured in average 7.1 years before cancer development. Cox-regression models were used to calculate hazard ratios (HRs) for VTE by WBC and neutrophil counts as categorized variables (80th percentile) with 95% confidence intervals (CIs). Results: During follow-up, 1720 subjects developed cancer and there were 388 VTE events, of which 116 occurred in the cancer-group (6.9 per 1000 person-years) and 272 in the cancer-free group (1.1 per 1000 person-years). In those who developed cancer, WBC count above the 80th percentile (≥8.6x109 cells/L) was associated with a 2.4-fold higher risk (HR 2.36, 95% CI: 1.44-3.87) of VTE compared to WBC count below the 40th percentile (<6.4x109 cells/L). No association was found between WBC count and VTE in those who stayed cancer-free (HR 0.94, 95% CI 0.65-1.36). Similar findings were observed for neutrophils. Comment: Pre-cancer WBC count was associated with risk of VTE in cancer patients, but not in cancer-free subjects. Our findings suggest that leukocytes may play a causal role in cancer-related VTE rather than only reflecting the low-grade inflammation associated with cancer

Consumption of oral anticancer drugs in Norway compared by different units of measurements – introduction of new DDDs

Background: Antineoplastic agents (ATC group L01) have not been assigned DDDs due to highly interindividual variation in dosages. Consumption data has therefore been presented in other measurement units such as grams of active ingredient. However, the protein kinase inhibitors (PKIs) are a rapidly growing drug group that was introduced to the market recently and are administered orally in a fixed dose. DDDs were therefore established for the PKIs in 2020. In this study we aim to assess whether the newly assigned DDDs would better express drug utilisation patterns in Norway than the current units of measurement. Methods: Sales data for PKIs (ATC level L01E) by grams, cost, units and packages for 2019 were collected from the Norwegian Drug Wholesales Statistics and data on number of prescriptions and prevalence for 2019 were collected from the Norwegian Prescription Database (NorPD). DDDs were calculated by applying the values of the new DDDs. Results: The proportions of the different substances varied according to the unit of measurement. DDDs and packages had the highest similarity and correlated better than grams with the prevalence of use in the Norwegian population. BCR-ABL tyrosine kinase inhibitors was the largest group accounting for 31% of the total consumption (DDD/1000 inhabitants/day) and imatinib was the most sold PKI in all units of measurement except cost. Conclusions: Using an international agreed unit of measurement gives reliability to the study result. Assignment of DDDs to PKIs will improve the quality of drug utilisation studies in this area

WBC count and risk of venous thromboembolism.

<p>Dose–response relationship between WBC count and risk of VTE in cancer and non-cancer subjects obtained by generalized linear regression. The regression models are adjusted for age, sex, BMI, smoking, self-reported diabetes, physical activity and self-reported CVD. The solid lines show HRs and the shaded areas show 95% CIs. Density plots show the distribution of WBC, and white vertical lines indicate 2.5^th, 25^th, 50^th, 75^th and 97.5^th percentiles.</p

Incidence rates (IRs) and hazard ratios (HRs) for symptomatic venous thromboembolism by increasing platelet count with 95% confidence intervals; The Tromsø Study 1994–2009.

<p>*10⁹/L.</p>†<p>Person years. Subjects who develop cancer during follow-up are treated as non-cancer subjects until one year prior to the cancer diagnosis.</p>‡<p>Incidence per 1000 person years.</p><p>Model 1: Adjusted for age and sex.</p><p>Model 2: Adjusted for age, sex, body mass index, smoking, leukocyte count and mean platelet volume.</p><p>Model 3: Model 2+ cancer stage (defined as localized or disseminated disease).</p

How Long Is a Normal Labor? Contemporary Patterns of Labor and Birth in a Low-Risk Sample of 1,612 Women from Four Nordic Countries

Objective: Normal progress of labor is a subject for discussion among professionals. The aim of this study was to assess the duration of labor in women with a planned home birth and spontaneous onset who gave birth at home or in hospital after transfer. Methods: This is a population-based study of home births in four Nordic countries (Denmark, Iceland, Norway, and Sweden). All midwives assisting at a home birth from 2008 to 2013 were asked to provide information about home births using a questionnaire. Results: Birth data from 1,612 women, from Denmark ( n = 1,170), Norway ( n = 263), Sweden ( n = 138), and Iceland ( n = 41) were included. The total median duration from onset of labor until the birth of the baby was approximately 14 hours for primiparas and 7.25 hours for multiparas. The duration of the different phases varied between countries. Blood loss more than 1,000 mL and perineal ruptures that needed suturing were associated with a longer pushing phase and the latter with country of residence, parity, single status, and the baby ’ s weight. Conclusion: In this population of healthy women with a low prevalence of interventions, the total duration of labor was fairly similar to what is described in the literature for multiparas, but longer for primiparas. Although the duration of the phases of labor differed among countries, it was to a minor extent associated with severe outcomes. (BIRTH 42:4 December 2015