Abstract
Aims
In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether ...this benefit was consistent in relation to background HF therapy.
Methods and results
In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and <50% of target dose). We analysed the primary composite endpoint of cardiovascular death or a worsening HF event. Most randomized patients (n = 4744) were treated with a diuretic (84%), renin–angiotensin system (RAS) blocker (94%), and BB (96%); 52% of those taking a BB and 38% taking a RAS blocker were treated with ≥50% of the recommended dose. Overall, the dapagliflozin vs. placebo hazard ratio (HR) was 0.74 95% confidence interval (CI) 0.65–0.85 for the primary composite endpoint (P < 0.0001). The effect of dapagliflozin was consistent across all subgroups examined: the HR ranged from 0.57 to 0.86 for primary endpoint, with no significant randomized treatment-by-subgroup interaction. For example, the HR in patients taking a RAS blocker, BB, and MRA at baseline was 0.72 (95% CI 0.61–0.86) compared with 0.77 (95% CI 0.63–0.94) in those not on all three of these treatments (P-interaction 0.64).
Conclusion
The benefit of dapagliflozin was consistent regardless of background therapy for HF.
This review discusses magnetomotive ultrasound, which is an emerging technique that uses superparamagnetic iron oxide nanoparticles as a contrast agent. The key advantage of using nanoparticle-based ...contrast agents is their ability to reach extravascular targets, whereas commercial contrast agents for ultrasound comprise microbubbles confined to the blood stream. This also extends possibilities for molecular imaging, where the contrast agent is labeled with specific targeting molecules (e.g., antibodies) so that pathologic tissue may be visualized directly. The principle of action is that an external time-varying magnetic field acts to displace the nanoparticles lodged in tissue and thereby their immediate surrounding. This movement is then detected with ultrasound using frequency- or time-domain analysis of echo data. As a contrast agent already approved for magnetic resonance imaging (MRI) by the US Food and Drug Administration, there is a shorter path to clinical translation, although safety studies of magnetomotion are necessary, especially if particle design is altered to affect biodistribution or signal strength. The external modulated magnetic field may be generated by electromagnets, permanent magnets, or a combination of the two. The induced nanoparticle motion may also reveal mechanical material properties of tissue, healthy or diseased, one of several interesting potential future aspects of the technique.
The Forward Physics Facility (FPF) is a proposal to create a cavern with the space and infrastructure to support a suite of far-forward experiments at the Large Hadron Collider during the High ...Luminosity era. Located along the beam collision axis and shielded from the interaction point by at least 100 m of concrete and rock, the FPF will house experiments that will detect particles outside the acceptance of the existing large LHC experiments and will observe rare and exotic processes in an extremely low-background environment. In this work, we summarize the current status of plans for the FPF, including recent progress in civil engineering in identifying promising sites for the FPF and the experiments currently envisioned to realize the FPF’s physics potential. We then review the many Standard Model and new physics topics that will be advanced by the FPF, including searches for long-lived particles, probes of dark matter and dark sectors, high-statistics studies of TeV neutrinos of all three flavors, aspects of perturbative and non-perturbative QCD, and high-energy astroparticle physics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart ...Failure (DAPA-HF) trial. This report explores the effect of dapagliflozin on incident type 2 diabetes (T2D) in the cohort without diabetes enrolled in the trial.
The subgroup of 2,605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and an HbA
of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new-onset diabetes was accomplished through periodic HbA
testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model.
At baseline, the mean HbA
was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93 of 1,307 patients (7.1%) in the placebo group and 64 of 1,298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (hazard ratio 0.68, 95% CI 0.50-0.94;
= 0.019). More than 95% of the participants who developed T2D had prediabetes at baseline (HbA
5.7-6.4%). Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not.
In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.
BACKGROUND:Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and ...quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), sodium–glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ).
METHODS:KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months.
RESULTS:A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 interquartile range, 58.3–91.7). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertilehazard ratio, 0.70 95% CI, 0.57–0.86; hazard ratio, 0.77 95% CI, 0.61–0.98; hazard ratio, 0.62 95% CI, 0.46–0.83; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P<0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 95% CI, 0.78–0.90; P<0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 95% CI, 1.08–1.23; odds ratio, 1.15 95% CI, 1.08–1.22; odds ratio, 1.14 95% CI, 1.07–1.22; number needed to treat=14, 15, and 18, respectively; P<0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score).
CONCLUSIONS:Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT03036124.
In a post hoc analysis, the frequency of occurrence of an early decline (dip) in estimated glomerular filtration rate (eGFR) after initiation of dapagliflozin and its association with outcomes were ...evaluated in patients with heart failure and reduced ejection fraction randomized in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial.
Patients with heart failure with reduced ejection fraction with or without type 2 diabetes and an eGFR ≥30 mL·min
·1.73 m
were randomized to placebo or dapagliflozin 10 mg daily. The primary outcome was the composite of worsening heart failure or cardiovascular death. The extent of the dip in eGFR between baseline and 2 weeks, patient characteristics associated with a >10% decline, and cardiovascular outcomes and eGFR slopes in participants experiencing this decline were investigated. Time-to-event outcomes were assessed in Cox regression from 14 days; eGFR slopes were assessed with repeated-measures mixed-effect models.
The mean change in eGFR between day 0 and 14 was -1.1 mL·min
·1.73 m
(95% CI, -1.5 to -0.7) with placebo and -4.2 mL·min
·1.73 m
(95% CI, -4.6 to -3.9) with dapagliflozin, giving a between-treatment difference of 3.1 mL·min
·1.73 m
(95% CI, 2.6-3.7). The proportions of patients randomized to dapagliflozin experiencing a >10%, >20%, and >30% decline in eGFR were 38.2%, 12.6%, and 3.4%, respectively; for placebo, they were 21.0%, 6.4%, and 1.3%, respectively. The odds ratio for a >10% early decline in eGFR with dapagliflozin compared with placebo was 2.36 (95% CI, 2.07-2.69;
<0.001). Baseline characteristics associated with a >10% decline in eGFR on dapagliflozin were older age, lower eGFR, higher ejection fraction, and type 2 diabetes. The hazard ratio for the primary outcome in patients in the placebo group experiencing a >10% decline in eGFR compared with ≤10% decline in eGFR was 1.45 (95% CI, 1.19-1.78). The corresponding hazard ratio in the dapagliflozin group was 0.73 (95% CI, 0.59-0.91;
<0.001). A >10% initial decline in eGFR was not associated with greater long-term decline in eGFR or more adverse events.
The average dip in eGFR after dapagliflozin was started was small and associated with better clinical outcomes compared with a similar decline on placebo in patients with heart failure with reduced ejection fraction. Large declines in eGFR were uncommon with dapagliflozin.
URL: https://www.
gov; Unique identifier: NCT03036124.
The deubiquitinase (DUB) ubiquitin‐specific protease 14 (USP14) is a dual domain protein that plays a regulatory role in proteasomal degradation and has been identified as a promising therapeutic ...target. USP14 comprises a conserved USP domain and a ubiquitin‐like (Ubl) domain separated by a 25‐residue linker. The enzyme activity of USP14 is autoinhibited in solution, but is enhanced when bound to the proteasome, where the Ubl and USP domains of USP14 bind to the Rpn1 and Rpt1/Rpt2 units, respectively. No structure of full‐length USP14 in the absence of proteasome has yet been presented, however, earlier work has described how transient interactions between Ubl and USP domains in USP4 and USP7 regulate DUB activity. To better understand the roles of the Ubl and USP domains in USP14, we studied the Ubl domain alone and in full‐length USP14 by nuclear magnetic resonance spectroscopy and used small angle x‐ray scattering and molecular modeling to visualize the entire USP14 protein ensemble. Jointly, our results show how transient interdomain interactions between the Ubl and USP domains of USP14 predispose its conformational ensemble for proteasome binding, which may have functional implications for proteasome regulation and may be exploited in the design of future USP14 inhibitors.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease that complicates pharmacological management and is associated with worse outcomes. We assessed the ...safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure). We also examined the effect of dapagliflozin on kidney function after randomization.
Patients who have HFrEF with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL·min
·1.73 m
were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) according to eGFR category at baseline (<60 and ≥60 mL·min
·1.73 m
) and used eGFR at baseline as a continuous measure, as well. Secondary cardiovascular outcomes and a prespecified composite renal outcome (≥50% sustained decline eGFR, end-stage renal disease, or renal death) were also examined, along with a decline in eGFR over time.
Of 4742 patients with a baseline eGFR, 1926 (41%) had eGFR <60 mL·min
·1.73 m
. The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% CI) for the primary end point in patients with chronic kidney disease was 0.71 (0.59-0.86) versus 0.77 (0.64-0.93) in those with an eGFR ≥60 mL·min
·1.73 m
(interaction
=0.54). The composite renal outcome was not reduced by dapagliflozin (hazard ratio=0.71 95% CI, 0.44-1.16;
=0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, -1.09 (-1.40 to -0.77) versus placebo -2.85 (-3.17 to -2.53) mL·min
·1.73 m
per year (
<0.001). This was observed in those with and without type 2 diabetes (
for interaction=0.92).
Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF, and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
BACKGROUND:The DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) showed that dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality ...and heart failure hospitalization and improved symptoms in patients with heart failure and reduced ejection fraction. We examined the effects of dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly.
METHODS:Patients in New York Heart Association functional class II or greater with a left ventricular ejection fraction ≤40% and a modest elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide) were eligible. Key exclusion criteria included systolic blood pressure <95 mm Hg and estimated glomerular filtration rate <30 mL·min·1.73 m. The primary outcome was the composite of an episode of worsening heart failure (heart failure hospitalization or urgent heart failure visit) or cardiovascular death, whichever occurred first.
RESULTS:A total of 4744 patients 22 to 94 years of age (mean age, 66.3 SD 10.9 years) were randomized636 patients (13.4%) were <55 years of age, 1242 (26.2%) were 55 to 64 years of age, 1717 (36.2%) were 65 to 74 years of age, and 1149 (24.2%) were ≥75 years of age. The rate of the primary outcome (per 100 person-years, placebo arm) in each age group was 13.6 (95% CI, 10.4–17.9), 15.7 (95% CI, 13.2–18.7), 15.1 (95% CI, 13.1–17.5), and 18.0 (95% CI, 15.2–21.4) with corresponding dapagliflozin/placebo hazard ratios of 0.87 (95% CI, 0.60–1.28), 0.71 (95% CI, 0.55–0.93), 0.76 (95% CI, 0.61–0.95), and 0.68 (95% CI, 0.53–0.88; P for interaction=0.76). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and symptoms. Although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group.
CONCLUSIONS:Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of age studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT03036124.
This study presents findings from a qualitative case study where principals ( n = 193), studying a national principal training programme, participated in a study exploring novice principals’ ...perceptions of how their leadership was impacted during the recent Covid-19 pandemic. A model classification of stressful situations related to coping strategies was used as the theoretical framework for the study and used in the content analysis with a deductive approach. In small groups, the principals used a specific conversation model and discussed their experiences of how their leadership had been affected during the pandemic. The findings showed that principals identified a lack of clarity and situations linked to the adaption to new rules required over time when staff and student absenteeism were consistent challenges. The majority of situations that the principals described can be linked to unclear but affectable situations, where they had to make uncomfortable decisions but also provide security and solutions. Principals mainly used problem-oriented stress management strategies by searching for information, analysing and finding new solutions.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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