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"Bloomfield, Beth"
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NO OWEN
If [Priscilla Owen] is confirmed, she will receive a lifetime appointment on the 5th U.S. Circuit Court of Appeals. In her current position on the Texas Supreme Court, she has participated in the only consideration of a federal court to hold that a two-parent consent statute with adequate judicial bypass is constitutional.
Newspaper Article
Rolofylline, an Adenosine A1−Receptor Antagonist, in Acute Heart Failure
Acute heart failure is a serious disorder often associated with progressive renal dysfunction. In this clinical trial, rolofylline, an adenosine A1–receptor antagonist, did not appear to benefit patients with acute heart failure and renal dysfunction.
Preexisting chronic kidney disease and worsening renal function are common in patients hospitalized with acute heart failure and are associated with poor outcomes.
1
–
5
Multiple factors are responsible for this association,
3
–
5
including coexisting conditions, less use of effective therapies in patients with renal dysfunction than in patients without renal dysfunction, and inadequate treatment of volume overload because of a suboptimal response to diuretics or concern regarding diuretic toxicity.
4
,
5
Adenosine has been implicated as an important intrarenal mediator of both worsening renal function and diuretic resistance.
6
,
7
ATP hydrolysis releases free adenosine into the extracellular space, which in turn . . .
Journal Article
Blood urea nitrogen-to-creatinine ratio in the general population and in patients with acute heart failure
ObjectiveThe blood urea nitrogen-to-creatinine (BUN/creatinine) ratio has been proposed as a useful parameter in acute heart failure (AHF), but data on the normal range and the added value of the ratio compared with its separate components in patients with AHF are lacking. The aim of this study is to define the normal range of BUN/creatinine ratio and to investigate its clinical significance in patients with AHF.MethodsIn 4484 subjects from the general population without cardiovascular comorbidities, we calculated age-specific and sex-specific normal values of the BUN/creatinine ratio, deriving a higher and lower than normal range of BUN/creatinine ratio (exceeding the 95% prediction intervals). Association of abnormal range to prognosis was tested in 2033 patients with AHF for the outcome of all-cause death through 180 days, death or cardiovascular or renal rehospitalisation through 60 days and heart failure (HF) rehospitalisation within 60 days.ResultsIn a cohort of patients with AHF, 482 (24.6%) and 28 (1.4%) patients with HF were classified into higher and lower than normal range groups, respectively. In Cox regression analysis, higher than normal range of BUN/creatinine ratio group was an independent predictor for all-cause death (HR: 1.86, 95% CI 1.29 to 2.66) and death or cardiovascular or renal rehospitalisation (HR: 1.37, 95% CI 1.03 to 1.82), but not for HF rehospitalisation (HR: 1.23, 95% CI 0.81 to 1.86) after adjustment for other prognostic factors including both creatinine and BUN.ConclusionsIn patients with AHF, BUN/creatinine higher than age-specific and sex-specific normal range is associated with worse prognosis independently from both creatinine and BUN.Clinical Trialsgov identifier NCT00328692 and NCT00354458
Journal Article
Serum Potassium Levels and Outcome in Acute Heart Failure (Data from the PROTECT and COACH Trials)
Serum potassium is routinely measured at admission for acute heart failure (AHF), but information on association with clinical variables and prognosis is limited. Potassium measurements at admission were available in 1,867 patients with AHF in the original cohort of 2,033 patients included in the Patients Hospitalized with acute heart failure and Volume Overload to Assess Treatment Effect on Congestion and Renal FuncTion trial. Patients were grouped according to low potassium (<3.5 mEq/l), normal potassium (3.5 to 5.0 mEq/l), and high potassium (>5.0 mEq/l) levels. Results were verified in a validation cohort of 1,023 patients. Mean age of patients was 71 ± 11 years, and 66% were men. Low potassium was present in 115 patients (6%), normal potassium in 1,576 (84%), and high potassium in 176 (9%). Potassium levels increased during hospitalization (0.18 ± 0.69 mEq/l). Patients with high potassium more often used angiotensin-converting enzyme inhibitors and mineralocorticoid receptor antagonists before admission, had impaired baseline renal function and a better diuretic response (p = 0.005), independent of mineralocorticoid receptor antagonist usage. During 180-day follow-up, a total of 330 patients (18%) died. Potassium levels at admission showed a univariate linear association with mortality (hazard ratio [log] 2.36, 95% confidence interval 1.07 to 5.23; p = 0.034) but not after multivariate adjustment. Changes of potassium levels during hospitalization or potassium levels at discharge were not associated with outcome after multivariate analysis. Results in the validation cohort were similar to the index cohort. In conclusion, high potassium levels at admission are associated with an impaired renal function but a better diuretic response. Changes in potassium levels are common, and overall levels increase during hospitalization. In conclusion, potassium levels at admission or its change during hospitalization are not associated with mortality after multivariate adjustment.
Journal Article
Plasma Neutrophil Gelatinase-Associated Lipocalin and Predicting Clinically Relevant Worsening Renal Function in Acute Heart Failure
The aim of this study was to evaluate the ability of Neutrophil Gelatinase-Associated Lipocalin (NGAL) to predict clinically relevant worsening renal function (WRF) in acute heart failure (AHF). Plasma NGAL and serum creatinine changes during the first 4 days of admission were investigated in 1447 patients hospitalized for AHF and enrolled in the Placebo-Controlled Randomized Study of the Selective A1Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) study. WRF was defined as serum creatinine rise ≥ 0.3 mg/dL through day 4. Biomarker patterns were described using linear mixed models. WRF developed in 325 patients (22%). Plasma NGAL did not rise earlier than creatinine in patients with WRF. After multivariable adjustment, baseline plasma NGAL, but not creatinine, predicted WRF. AUCs for WRF prediction were modest (<0.60) for all models. NGAL did not independently predict death or rehospitalization (p = n.s.). Patients with WRF and high baseline plasma NGAL had a greater risk of death, and renal or cardiovascular rehospitalization by 60 days than patients with WRF and a low baseline plasma NGAL (p for interaction = 0.024). A rise in plasma NGAL after baseline was associated with a worse outcome in patients with WRF, but not in patients without WRF (p = 0.007). On the basis of these results, plasma NGAL does not provide additional, clinically relevant information about the occurrence of WRF in patients with AHF.
Journal Article
A combined clinical and biomarker approach to predict diuretic response in acute heart failure
Background
Poor diuretic response in acute heart failure is related to poor clinical outcome. The underlying mechanisms and pathophysiology behind diuretic resistance are incompletely understood. We evaluated a combined approach using clinical characteristics and biomarkers to predict diuretic response in acute heart failure (AHF).
Methods and results
We investigated explanatory and predictive models for diuretic response—weight loss at day 4 per 40 mg of furosemide—in 974 patients with AHF included in the PROTECT trial. Biomarkers, addressing multiple pathophysiological pathways, were determined at baseline and after 24 h. An explanatory baseline biomarker model of a poor diuretic response included low potassium, chloride, hemoglobin, myeloperoxidase, and high blood urea nitrogen, albumin, triglycerides, ST2 and neutrophil gelatinase-associated lipocalin (
r
2
= 0.086). Diuretic response after 24 h (early diuretic response) was a strong predictor of diuretic response (
β
= 0.467,
P
< 0.001;
r
2
= 0.523). Addition of diuretic response after 24 h to biomarkers and clinical characteristics significantly improved the predictive model (
r
2
= 0.586,
P
< 0.001).
Conclusions
Biomarkers indicate that diuretic unresponsiveness is associated with an atherosclerotic profile with abnormal renal function and electrolytes. However, predicting diuretic response is difficult and biomarkers have limited additive value. Patients at risk of poor diuretic response can be identified by measuring early diuretic response after 24 h.
Journal Article
Identifying Subpopulations with Distinct Response to Treatment Using Plasma Biomarkers in Acute Heart Failure: Results from the PROTECT Trial
Background
Over the last 50 years, clinical trials of novel interventions for acute heart failure (AHF) have, with few exceptions, been neutral or shown harm. We hypothesize that this might be related to a differential response to pharmacological therapy.
Methods
We studied the magnitude of treatment effect of rolofylline across clinical characteristics and plasma biomarkers in 2033 AHF patients and derived a biomarker-based responder sum score model. Treatment response was survival from all-cause mortality through day 180.
Results
In the overall study population, rolofylline had no effect on mortality (HR 1.03, 95% CI 0.82–1.28,
p
= 0.808). We found no treatment interaction across clinical characteristics, but we found interactions between several biomarkers and rolofylline. The biomarker-based sum score model included TNF-R1α, ST2, WAP four-disulfide core domain protein HE4 (WAP-4C), and total cholesterol, and the score ranged between 0 and 4. In patients with score 4 (those with increased TNF-R1α, ST2, WAP-4C, and low total cholesterol), treatment with rolofylline was beneficial (HR 0.61, 95% CI 0.40–0.92,
p
= 0.019). In patients with score 0, treatment with rolofylline was harmful (HR 5.52, 95% CI 1.68–18.13,
p
= 0.005; treatment by score interaction
p
< 0.001). Internal validation estimated similar hazard ratio estimates (0 points: HR 5.56, 95% CI 5.27–7–5.87; 1 point: HR 1.31, 95% CI 1.25–1.33; 2 points: HR 0.75, 95% CI 0.74–0.76; 3 points: HR 1.13, 95% CI 1.11–1.15; 4 points, HR 0.61, 95% CI 0.61–0.62) compared to the original data.
Conclusion
Biomarkers are superior to clinical characteristics to study treatment heterogeneity in acute heart failure.
Journal Article
Setting the agenda for social science research on the human microbiome
There is increasing concern globally about the enormity of the threats posed by antimicrobial resistance (AMR) to human, animal, plant and environmental health. A proliferation of international, national and institutional reports on the problems posed by AMR and the need for antibiotic stewardship have galvanised attention on the global stage. However, the AMR community increasingly laments a lack of action, often identified as an ‘implementation gap’. At a policy level, the design of internationally salient solutions that are able to address AMR’s interconnected biological and social (historical, political, economic and cultural) dimensions is not straightforward. This multidisciplinary paper responds by asking two basic questions: (A) Is a universal approach to AMR policy and antibiotic stewardship possible? (B) If yes, what hallmarks characterise ‘good’ antibiotic policy? Our multistage analysis revealed four central challenges facing current international antibiotic policy: metrics, prioritisation, implementation and inequality. In response to this diagnosis, we propose three hallmarks that can support robust international antibiotic policy. Emerging hallmarks for good antibiotic policies are: Structural, Equitable and Tracked. We describe these hallmarks and propose their consideration should aid the design and evaluation of international antibiotic policies with maximal benefit at both local and international scales.
Journal Article