| 1. |
- Munch, Marie W., et al.
(författare)
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Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomized Trial
- 2021
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Ingår i: Journal of the American Medical Association (JAMA). - : AMER MEDICAL ASSOC. - 0098-7484 .- 1538-3598. ; 326:18, s. 1807-1817
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Tidskriftsartikel (refereegranskat)abstract
- Question What is the effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support at 28 days in patients with COVID-19 and severe hypoxemia? Findings In this randomized trial that included 1000 patients with COVID-19 and severe hypoxemia, treatment with 12 mg/d of dexamethasone resulted in 22.0 days alive without life support at 28 days compared with 20.5 days in those receiving 6 mg/d of dexamethasone. This difference was not statistically significant. Meaning Compared with 6 mg of dexamethasone, 12 mg of dexamethasone did not statistically significantly reduce the number of days alive without life support at 28 days. This multicenter randomized clinical trial compares the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. IMPORTANCE A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. OBJECTIVE To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. INTERVENTIONS Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and >= 1 serious adverse reactions at 28 days). RESULTS Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.
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| 2. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 3. |
- Erhardt, Tobias, et al.
(författare)
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High-resolution aerosol data from the top 3.8kyr of the East Greenland Ice coring Project (EGRIP) ice core
- 2023
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Ingår i: Earth System Science Data. - 1866-3508. ; 15:11, s. 5079-5091
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Tidskriftsartikel (refereegranskat)abstract
- Here we present the high-resolution continuous flow analysis (CFA) data from the top 479m of the East Greenland Ice coring Project (EGRIP) ice core covering the past 3.8kyr. The data consist of 1mm depth-resolution profiles of calcium, sodium, ammonium, nitrate, and electrolytic conductivity as well as decadal averages of these profiles. The nominally 1mm data represent an oversampling of the record as the true resolution is limited by the analytical setup to approximately 1cm. Alongside the data we provide a description of the measurement setup, procedures, the relevant references for the specific methods as well as an assessment of the precision of the measurements, the sample-to-depth assignment, and the depth and temporal resolution of the data set. The error in absolute depth assignment of the data may be on the order of 2cm; however, relative depth offsets between the records of the individual species are only on the order of 1mm. The presented data have sub-annual resolution over the entire depth range and have already formed part of the data for an annually layer-counted timescale for the EGRIP ice core used to improve and revise the multi-core Greenland ice-core chronology (GICC05) to a new version, GICC21 . The data are available in full 1mm resolution and decadal averages on PANGAEA (10.1594/PANGAEA.945293, ).
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| 4. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 5. |
- Kjær, Kurt H., et al.
(författare)
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Glacier response to the Little Ice Age during the Neoglacial cooling in Greenland
- 2022
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Ingår i: Earth-Science Reviews. - : Elsevier. - 0012-8252 .- 1872-6828. ; 227
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Tidskriftsartikel (refereegranskat)abstract
- In the Northern Hemisphere, an insolation driven Early to Middle Holocene Thermal Maximum was followed by a Neoglacial cooling that culminated during the Little Ice Age (LIA). Here, we review the glacier response to this Neoglacial cooling in Greenland. Changes in the ice margins of outlet glaciers from the Greenland Ice Sheet as well as local glaciers and ice caps are synthesized Greenland-wide. In addition, we compare temperature reconstructions from ice cores, elevation changes of the ice sheet across Greenland and oceanographic reconstructions from marine sediment cores over the past 5,000 years. The data are derived from a comprehensive review of the literature supplemented with unpublished reports. Our review provides a synthesis of the sensitivity of the Greenland ice margins and their variability, which is critical to understanding how Neoglacial glacier activity was interrupted by the current anthropogenic warming. We have reconstructed three distinct periods of glacier expansion from our compilation: two older Neoglacial advances at 2,500 – 1,700 yrs. BP (Before Present = 1950 CE, Common Era) and 1,250 – 950 yrs. BP; followed by a general advance during the younger Neoglacial between 700-50 yrs. BP, which represents the LIA. There is still insufficient data to outline the detailed spatio-temporal relationships between these periods of glacier expansion. Many glaciers advanced early in the Neoglacial and persisted in close proximity to their present-day position until the end of the LIA. Thus, the LIA response to Northern Hemisphere cooling must be seen within the wider context of the entire Neoglacial period of the past 5,000 years. Ice expansion appears to be closely linked to changes in ice sheet elevation, accumulation, and temperature as well as surface-water cooling in the surrounding oceans. At least for the two youngest Neoglacial advances, volcanic forcing triggering a sea-ice /ocean feedback, could explain their initiation. There are probably several LIA glacier fluctuations since the first culmination close to 1250 CE (Common Era) and available data suggests ice culminations in the 1400s, early to mid-1700s and early to mid-1800s CE. The last LIA maxima lasted until the present deglaciation commenced around 50 yrs. BP (1900 CE). The constraints provided here on the timing and magnitude of LIA glacier fluctuations delivers a more realistic background validation for modelling future ice sheet stability.
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| 6. |
- Mortensen, Camilla Bekker, et al.
(författare)
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Long-term outcomes with haloperidol versus placebo in acutely admitted adult ICU patients with delirium
- 2024
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Ingår i: Intensive Care Medicine. - 0342-4642. ; 50:1, s. 103-113
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We assessed long-term outcomes in acutely admitted adult patients with delirium treated in intensive care unit (ICU) with haloperidol versus placebo. Methods: We conducted pre-planned analyses of 1-year outcomes in the Agents Intervening against Delirium in the ICU (AID-ICU) trial, including mortality and health-related quality of life (HRQoL) assessed by Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS) (deceased patients were assigned the numeric value zero). Outcomes were analysed using logistic and linear regressions with bootstrapping and G-computation, all with adjustment for the stratification variables (site and delirium motor subtype) and multiple imputations for missing HRQoL values. Results: At 1-year follow-up, we obtained vital status for 96.2% and HRQoL data for 83.3% of the 1000 randomised patients. One-year mortality was 224/501 (44.7%) in the haloperidol group versus 251/486 (51.6%) in the placebo group, with an adjusted absolute risk difference of − 6.4%-points (95% confidence interval [CI] − 12.8%-points to − 0.2%-points; P = 0.045). These results were largely consistent across the secondary analyses. For HRQoL, the adjusted mean differences were 0.04 (95% CI − 0.03 to 0.11; P = 0.091) for EQ-5D-5L-5L index values, and 3.3 (95% CI − 9.3 to 17.5; P = 0.142) for EQ VAS. Conclusions: In acutely admitted adult ICU patients with delirium, haloperidol treatment reduced mortality at 1-year follow-up, but did not statistically significantly improve HRQoL.
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| 7. |
- Sinnl, Giulia, et al.
(författare)
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A multi-ice-core, annual-layer-counted Greenland ice-core chronology for the last 3800 years : GICC21
- 2022
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 18:5, s. 1125-1150
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Tidskriftsartikel (refereegranskat)abstract
- Ice-core timescales are vital for the understanding of past climate; hence they should be updated whenever significant amounts of new data become available. Here, the Greenland ice-core chronology GICC05 was revised for the last 3835 years by synchronizing six deep ice cores and three shallow ice cores from the central Greenland ice sheet. A new method was applied by combining automated counting of annual layers on multiple parallel proxies and manual fine-tuning. A layer counting bias was found in all ice cores because of site-specific signal disturbances; therefore the manual comparison of all ice cores was deemed necessary to increase timescale accuracy. After examining sources of error and their correlation lengths, the uncertainty rate was quantified to be 1 year per century. The new timescale is younger than GICC05 by about 13 years at 3835 years ago. The most recent 800 years are largely unaffected by the revision. Between 800 and 2000 years ago, the offset between timescales increases steadily, with the steepest offset occurring between 800 and 1100 years ago. Moreover, offset oscillations of about 5 years around the average are observed between 2500 and 3800 years ago. The non-linear offset behavior is attributed to previous mismatches of volcanic eruptions, to the much more extensive dataset available to this study, and to the finer resolution of the new ice-core ammonium matching. By analysis of the common variations in cosmogenic radionuclides, the new ice-core timescale is found to be in alignment with the IntCal20 curve (Reimer et al., 2020).
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