Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction.

Aims: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. Methods and results: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18–96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33–1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted

Report of the direct infrared sensors panel

The direct infrared sensors panel considered a wide range of options for technologies relevant to the science goals of the Astrotech 21 mission set. Among the technologies assessed are: large format arrays; photon counting detectors; higher temperature 1 to 10 micro-m arrays; impurity band conduction (IBC) or blocked impurity band (BIB) detectors; readout electronics; and adapting the Space Infrared Telescope Facility and Hubble Space Telescope. Detailed development plans were presented for each of these technology areas

Dietary Protein Deficiency and Mycobacterium Bovis BCG Affect Interleukin-2 Activity in Experimental Pulmonary Tuberculosis

Inbred strain 2 guinea pigs were vaccinated with Mycobacterium bovis BCG or were left unvaccinated. They were maintained for 6 weeks on defined, isocaloric diets containing either 30% (control animals) or 10% (animals receiving low protein) ovalbumin as the sole protein source. Animals were challenged by the respiratory route with a low dose of virulent M. tuberculosis H37Rv and killed 4 weeks later. Protein-malnourished animals were not protected by previous vaccination with BCG. Lymphocytes isolated from various tissues were tested in vitro for proliferative responses to mitogen (concanavalin A) and antigen (purified protein derivative [PPD]), production of interleukin-2 (IL-2), and response to exogenous recombinant IL-2 (rIL-2). Protein-malnourished guinea pigs responded only weakly to PPD skin tests, and their blood and lymph node lymphocytes exhibited impaired proliferation when cultured with PPD in vitro. IL-2 levels were consistently low in cultures of stimulated blood and spleen lymphocytes from protein-deprived animals. BCG vaccination of nutritionally normal guinea pigs, on the other hand, induced significantly more IL-2 production by PPD- and concanavalin A-stimulated lymphocytes. The addition of exogenous mouse rIL-2 (40 and 80 U/ml) in vitro to PPD-stimulated blood and lymph node cells from nonvaccinated, protein-deprived guinea pigs resulted in no improvement of the proliferative response. Previous vaccination of malnourished guinea pigs did not consistently enhance the response of PPD-stimulated lymphocytes to added rIL-2. Dietary protein deficiency and BCG vaccination appear to modulate antigen-driven cellular immunity in animals with tuberculosis by altering the production of, and the response to, IL-2 by PPD-stimulated lymphocytes

Care transitions for older patients with musculoskeletal disorders: continuity from the providers’ perspective

<p><strong>Introduction</strong>: Care transitions are a common and frequently adverse aspect of health care, resulting in a high-risk period for both care quality and patient safety. Patients who have complex care needs and undergo treatment in multiple care settings, such as older patients with musculoskeletal disorders, may be at higher risk for poor care transitions.</p><p><strong>Methods: </strong>Key informant interviews were used to gather in-depth information on transitional care issues, particularly those which impact informational continuity, from the perspective of a range of health professionals (η=17) in care settings relevant to the care continuum of older patients with hip fractures.</p><p><strong>Results:</strong> Three transitional care themes were identified; medical complexity impacts care trajectories, larger circles of care can be both beneficial and challenging, and a variety of channels and modes are required for meaningful information exchange. Many issues cut across each care setting, and address challenges to informational continuity among and between health care providers, patients, and caregivers.</p><p><strong>Conclusions:</strong> Medical complexity enlarges the circle of care which challenges care continuity. There may be fundamental elements which, regardless of care setting, strengthen transitional care quality. Standardized transitional care processes might help to offset informational discontinuity across care settings as a result of this population's larger circles of care.</p

C-Reactive protein and risk of ESRD: results from the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT)

Background: To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). Study Design Post hoc analysis of a randomized controlled trial. Setting &#38; Participants: 4,038 patients with type 2 diabetes, CKD, and anemia in TREAT. Predictor: Baseline serum CRP concentrations. Outcomes: The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD. Measurements: We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest. Results: Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels &gt; 3.0 mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels ≤ 3.0 mg/L, those with moderately/markedly elevated CRP levels (≥6.9 mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models. Limitations: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Conclusions: Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD

Valsartan for attenuating disease evolution in early sarcomeric hypertrophic cardiomyopathy: the design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial

Background: Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype. Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained

Prevalence of prediabetes and undiagnosed diabetes in patients with HFpEF and HFrEF and associated clinical outcomes

Purpose: The prevalence and consequences of prediabetic dysglycemia and undiagnosed diabetes is unknown in patients with heart failure (HF) and preserved ejection fraction (HFpEF) and has not been compared to heart failure and reduced ejection fraction (HFrEF). Methods: We examined the prevalence and outcomes associated with normoglycemia, prediabetic dysglycemia and diabetes (diagnosed and undiagnosed) among individuals with a baseline glycated hemoglobin (hemoglobin A1c, HbA1c) measurement stratified by HFrEF or HFpEF in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity programme (CHARM). We studied the primary outcome of HF hospitalization or cardiovascular (CV) death, and all-cause death, and estimated hazard ratios (HR) by use of multivariable Cox regression models. Results: HbA1c was measured at baseline in CHARM patients enrolled in the USA and Canada and was available in 1072/3023 (35%) of patients with HFpEF and 1578/4576 (34%) patients with HFrEF. 18 and 16% had normoglycemia (HbA1c &lt; 6.0), 20 and 22% had prediabetes (HbA1c 6.0–6.4), respectively. Finally among patients with HFpEF 22% had undiagnosed diabetes (HbA1c &gt; 6.4), and 40% had known diabetes (any HbA1c), with corresponding prevalence among HFrEF patients being 26 and 35%. The rates of both clinical outcomes of interest were higher in patients with undiagnosed diabetes and prediabetes, compared to normoglycemic patients, irrespective of HF subtype, and in general higher among HFrEF patients. For the primary composite outcome among HFpEF patients, the HRs were 1.02 (95% CI 0.63–1.65) for prediabetes, HR 1.18 (0.75–1.86) for undiagnosed diabetes and 2.75 (1.83–4.11) for known diabetes, respectively, p value for trend across groups &lt; 0.001. Dysglycemia was also associated with worse outcomes in HFrEF. Conclusions: These findings confirm the remarkably high prevalence of dysglycemia in heart failure irrespective of ejection fraction phenotype, and demonstrate that dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes and institution of glucose lowering therapy in patients with HFpEF as well as HFrEF

Renin–Angiotensin–Aldosterone System inhibitors in patients with Covid-19

No abstract available