The Effect of Fluctuating Temperature on the Stability of Turoctocog Alfa for Hemophilia A

Factor VIII (FVIII) is indicated for the prevention or treatment of bleeding in patients with hemophilia A. FVIII product stability under high and fluctuating temperatures is important, particularly for patients who reside in, or travel to, regions with high ambient temperatures, as they may remove their product from the refrigerator and return it, unused, multiple times. We evaluated the effect of variable temperature storage conditions, including up to 40 °C, on the stability of the recombinant FVIII product, turoctocog alfa

Recombinant FVIII Products (Turoctocog Alfa and Turoctocog Alfa Pegol) Stable Up to 40°C

Purpose: The stability under high-temperature conditions of factor VIII (FVIII) concentrates for replacement therapy is of critical importance to patients, particularly those who reside in, or travel to, regions with high ambient temperatures. Concerns about product stability may limit or prevent access to treatment for patients and may limit their ability to live a close-to-normal life. This study evaluated the effect of hot and humid storage conditions on the long-term stability of the recombinant FVIII products, turoctocog alfa and turoctocog alfa pegol. Methods: Turoctocog alfa samples were assessed for stability at 30°C for 9 months or 40°C for 3 months following storage at 5°C for 21 or 27 months, respectively, while turoctocog alfa pegol samples were assessed at 30°C for 12 months or 40°C for 3 months following storage at 5°C for 18 or 27 months, respectively. In addition, turoctocog alfa and turoctocog alfa pegol dry powders were evaluated for stability at 5°C/ambient humidity (AH) for 30 months, 30°C/75% relative humidity (RH) for 12 months and 40°C/75% RH for 6 months. Both studies utilized a range of product strengths. Key stability assessments included oxidized forms, potency, water content and high molecular weight protein (HMWP). Results: Both turoctocog alfa and turoctocog alfa pegol remained stable following storage at 40°C/75% RH for 3 months, and at single temperatures (5°C/AH, 30 and 40°C/75% RH), without any major increase in HMWP or any impairment of potency or water content. Conclusion: Turoctocog alfa and turoctocog alfa pegol offer stability at 40°C for up to 3 months without jeopardizing the quality of each product. These stability characteristics may offer patients flexibility with product storage and daily use

Physical Exercise during Pregnancy and the Risk of Preterm Birth: A Study within the Danish National Birth Cohort

According to many national recommendations, women should be physically active during pregnancy, but em-pirical evidence to support this recommendation is sparse. The authors ’ aim in this study was to examine the relation between physical exercise during pregnancy and the risk of preterm birth. Self-reported data on physical exercise during pregnancy were collected prospectively for 87,232 singleton pregnancies included in the Danish National Birth Cohort between 1996 and 2002. Hazard ratios for preterm birth according to hours of exercise per week, type of exercise, and metabolic equivalent-hours per week, respectively, were calculated using Cox re-gression analysis. Results showed a reduced risk of preterm birth among the almost 40 % of women who engaged in some kind of exercise during pregnancy in comparison with nonexercisers (hazard ratio 0.82, 95 % confidence interval: 0.76, 0.88), but no dose-response relation was seen. The association was not affected by the type of exercise, and the results were not altered when the degree of preterm birth was taken into account. These findings do not indicate any adverse effects of exercise on the risk of preterm birth and therefore do not contradict current recommendations. exercise; pregnancy; premature birth Abbreviations: CI, confidence interval; MET, metabolic equivalent. Health authorities in the United States, Great Britain

Temporal trends in stroke admissions in Denmark 1997–2009

BACKGROUND: The Stroke burden is increasing in many populations where health institutions may experience more patients. We wanted to examine whether incidence rates and absolute number of hospitalized stroke patients remained stable in Denmark during a 13 years period where exposure to major stroke risk factors decreased, changes in stroke treatment was implemented, and the age of the population increased. METHODS: The Danish National Patient Register was used to identify all subjects 25 years of age or above admitted with a first time stroke in Denmark from 1997–2009. Incidence rates (IRs) and age-adjusted Poisson regression analyses were used to examine trends in age-, gender- and stroke subtype (ischaemic or unspecified). RESULTS: During the 13-year observation period there were 53.5 million person-years at risk (PY) and a total of 84,626 male and 84,705 female stroke patients were admitted to Danish hospitals. The IRs of hospitalized strokes per 1000 PY was 3.21 (95% confidence interval [CI] 3.16-3.27) in 1997, 3.85 (95% CI 3.79-3.91) in 2003 and 3.22 (95% CI 3.16-3.28) in 2009, respectively. Incidence rate ratios of hospitalized stroke events adjusted for age in the period 2007–2009 compared to 1997–2000 were 0.89 (95% CI 0.87- 0.91) for men and 0.92 (95% CI 0.90-0.94) for women. The incidence of hospitalized unspecified strokes decreased from 1997 to 2009 whereas there was a steep rise in incidence for hospitalization with specified ischemic stroke during this period. CONCLUSION: This study found a constant rate of stroke hospitalization in Denmark from 1997–2009. The overall rate of hospitalized strokes adjusted for age decreased during this period

Gene Expressions and High Lymphocyte Count May Predict Durable Clinical Benefits in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

Background: Not all patients with advanced non-small cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs). Therefore, we aimed to assess the predictive potential of gene expression profiling (GEP), peripheral immune cell counts, and clinical characteristics. Methods: The primary endpoint of this prospective, observational study was a durable clinical benefit (DCB) defined as progression-free survival >6 months. In a subgroup with histological biopsies of sufficient quality (n = 25), GEP was performed using the nCounter® PanCancer IO 360 panel. Results: DCB was observed in 49% of 123 included patients. High absolute lymphocyte count (ALC) and absence of liver metastases were associated with DCB (OR = 1.95, p = 0.038 and OR = 0.36, p = 0.046, respectively). GEP showed clustering of differentially expressed genes according to DCB, and a strong association between PD-L1 assessed by GEP (CD274) and immunohistochemistry (IHC) was observed (p = 0.00013). The TGF-β, dendritic cell, and myeloid signature scores were higher for patients without DCB, whereas the JAK/STAT loss signature scores were higher for patients with DCB (unadjusted p-values 9/L and absence of liver metastases were significantly associated with DCB in ICI-treated patients with NSCLC. GEP was only feasible in 20% of the patients. GEP-derived signatures may be associated with clinical outcomes, and PD-L1 could be assessed by GEP rather than IHC

GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal

Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (β SD(SE) = −0.22 (0.03), p = 6.5 × 10 −12) and total cholesterol (−0.17 (0.03), p = 1.1 × 10 −8) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance. [Figure not available: see fulltext.].</p