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IMPORTANCE: Heart failure with recovered ejection fraction (HFrecEF) is a recently recognized phenotype of patients with a history of reduced left ventricular ejection fraction (LVEF) that has subsequently normalized. It is unknown whether such LVEF improvement is associated with improvements in health status. OBJECTIVE: To examine changes in health-related quality of life in patients with heart failure with reduced ejection fraction (HFrEF) whose LVEF normalized, compared with those whose LVEF remains reduced and those with HF with preserved EF (HFpEF). DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted at a tertiary care hospital from November 2016 to December 2018. Consecutive patients seen in a heart failure clinic who completed patient-reported outcome assessments were included. Clinical data were abstracted from the electronic health record. Data analysis was completed from February to December 2020. MAIN OUTCOMES AND MEASURES: Changes in Kansas City Cardiomyopathy Questionnaire overall summary score, Visual Analog Scale score, and Patient-Reported Outcomes Measurement Information System domain scores on physical function, fatigue, depression, and satisfaction with social roles over 1-year follow-up. RESULTS: The study group included 319 patients (mean [SD] age, 60.4 [15.5] years; 120 women [37.6%]). At baseline, 212 patients (66.5%) had HFrEF and 107 (33.5%) had HFpEF. At a median follow-up of 366 (interquartile range, 310-421) days, LVEF had increased to 50% or more in 35 patients with HFrEF (16.5%). Recovery of systolic function was associated with heart failure–associated quality-of-life improvement, such that for each 10% increase in LVEF, the Kansas City Cardiomyopathy Questionnaire score improved by an mean (SD) of 4.8 (1.6) points (P = .003). Recovery of LVEF was also associated with improvement of physical function, satisfaction with social roles, and a reduction in fatigue. CONCLUSIONS AND RELEVANCE: Among patients with HFrEF in this study, normalization of left ventricular systolic function was associated with a significant improvement in health-related quality of life.

Although the prevalence of sickle cell anemia is high in Haiti, treatment with hydroxyurea (HU) is uncommon. HU therapy was started at a hospital in Northern Haiti for children and young adults who had presented with complications of their disease. The patients were followed in clinic for their response to therapy and the principal outcome was hospitalization for complications. There was a 70% decrease in the rate of hospitalization in the cohort with no significant complications or deaths during the study period. Treatment with HU is a proven therapy that reduces the morbidity associated with sickle cell anemia and efforts should be made to assure access and affordability in regions with a high prevalence.

Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20–30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90?kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.

Background:Physician communication of lifetime risk prediction can improve patient understanding of atrial fibrillation (AF) risk and motivate lifestyle changes and preventive measures. Therefore, our objective was to assess how physicians perceive short-term and lifetime risks of atrial fibrillation (AF), using a survey.Methods:We invited American Heart Association (AHA) members to complete an online survey via email from November 2-22, 2021. Respondents were randomized to one of 32 vignettes characterized by AF risk factors (height, weight, current smoking, systolic blood pressure, diastolic blood pressure, use of antihypertensive medication, diabetes, history of heart failure, and history of myocardial infarction). Respondents were further randomized to either estimate the 5-year or lifetime AF risk on a 0-100% scale with 10% intervals (e.g., “10-19%”) or were shown the predicted 5-year or lifetime AF risk value and asked to pick the correct interpretation in a multiple-choice question.Results:Of 11,330 AHA professional members who received the emailed survey, 109 (1%) physicians responded (mean age 51 years, 33% women) (Table). Most respondents estimated the 5-year AF risk correctly (7/9, 78%) but none accurately estimated the lifetime risk (0/18, 0%). Most respondents interpreted the predicted 5-year risk correctly (21/28, 75%) but about half of respondents misinterpreted the lifetime risk (14/25, 56%).Conclusions:In a small sample of physicians, few respondents correctly estimated and interpreted the lifetime risk of AF, suggesting that physicians may not be familiar with this risk format. It may be necessary to study the frequency and manner in which physicians communicate lifetime risk of AF.

The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity.

The type 1 cannabinoid receptor (CB1) modulates numerous neurobehavioral processes and is therefore explored as a target for the treatment of several mental and neurological diseases. However, previous studies have investigated CB1 by targeting it globally, regardless of its two main neuronal localizations on glutamatergic and GABAergic neurons. In the context of cocaine addiction this lack of selectivity is critical since glutamatergic and GABAergic neuronal transmission is involved in different aspects of the disease. To determine whether CB1 exerts different control on cocaine seeking according to its two main neuronal localizations, we used mutant mice with deleted CB1 in cortical glutamatergic neurons (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1). In Glu-CB1, gene deletion concerns the dorsal telencephalon, including neocortex, paleocortex, archicortex, hippocampal formation and the cortical portions of the amygdala. In GABA-CB1, it concerns several cortical and non-cortical areas including the dorsal striatum, nucleus accumbens, thalamic, and hypothalamic nuclei. We tested complementary components of cocaine self-administration, separating the influence of primary and conditioned effects. Mechanisms underlying each phenotype were explored using in vivo microdialysis and ex vivo electrophysiology. We show that CB1 expression in forebrain GABAergic neurons controls mouse sensitivity to cocaine, while CB1 expression in cortical glutamatergic neurons controls associative learning processes. In accordance, in the nucleus accumbens, GABA-CB1 receptors control cocaine-induced dopamine release and Glu-CB1 receptors control AMPAR/NMDAR ratio; a marker of synaptic plasticity. Our findings demonstrate a critical distinction of the altered balance of Glu-CB1 and GABA-CB1 activity that could participate in the vulnerability to cocaine abuse and addiction. Moreover, these novel insights advance our understanding of CB1 neuropathophysiology.

The safety and efficacy of continuous, multiday, automated glycaemic management has not been tested in outpatient studies of preadolescent children with type 1 diabetes. We aimed to compare the safety and efficacy of a bihormonal bionic pancreas versus conventional insulin pump therapy in this population of patients in an outpatient setting.

•AMPK activation by GSK621 enhances preapoptotic surface exposure of CALR in AML.•AML cells primed by AMPK activation are potent dendritic cell activators, and induce anticancer immunity in vivo.

AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.

SUMMARY Until recently, the treatment of blood cancers has rested exclusively on chemotherapy, radiation and, in select cases, stem cell transplantation, giving rise to frequent and sometimes life-threatening side effects. The past 10 years have witnessed dramatic clinical advances due to the development of novel therapies, hereafter referred to as targeted therapies, which specifically inhibit molecules that are essential to the pathophysiology of individual malignancies. In this article, we will discuss the general concept of targeting signaling pathways in cancers and the limitations of this strategy, with a particular focus on the emergence of resistant cancer clones under the selective pressures exerted by targeted therapies. Finally, we will examine a number of targeted therapies with immediate application in contemporary clinical practice.

Social determinants of health, in particular education and income, influence the incidence, management, and outcomes of cardiovascular diseases including atrial fibrillation (AF). Data are limited on the associations of socioeconomic status with lifetime risk of incident AF.

AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitroand in vivostudies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML.

Background:The NIH-sponsored observational study “Comparative Study of Haiti and Miami Cohorts of Sickle Cell Disease CSHSCD” (R01HL149121) coordinates the follow up of children with sickle cell disease (SCD) in Haiti and compares it to a Miami cohort of children of either Haitian or African American ethnicity for the purpose of assessing barriers through questionnaires and examining differences in the care received in their respective environments.

Introduction:Social determinants of health, in particular education and income, influence the incidence, management, and outcomes of cardiovascular diseases including atrial fibrillation (AF). However, data are limited on the effect of socioeconomic status on the lifetime risk of incident AF. We assessed the association of income and education with lifetime risk of AF in the Framingham Heart Study (FHS).Methods:We selected 2172 FHS participants (51% women) who were free of AF at the index age of 55 years. We assessed educational attainment (some college or more) at the last exam prior to index age and household income ($40k/50k/55k or more depending on the FHS cohort). We estimated the lifetime risk of AF as the cumulative incidence of AF, accounting for the competing risk of death, at age 95 years. We analyzed strata defined by education and household income separately, and by combining education and household income. We adjusted analyses on sex, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, history of myocardial infarction, and history of heart failure.Results:Over a mean follow-up of 13 years, 265 participants developed incident AF. The lifetime risk of developing AF was 32.5% (95%CI, 26.5% to 38.5%) and 32.5% (95%CI, 28.7% to 38.3%) among participants with lower and higher education attainment (p=0.98). The lifetime risk of developing AF was 32.1% (95%CI, 26.7% to 37.5%) and 31.8% (95%CI, 26.6% to 36.9%) among participants with lower and higher household income (p=0.79). There was no evidence of an interaction between education and income on lifetime risk of AF (p = 0.84). Results were similar in subgroups of women and men.Conclusions:In our community-based sample, there was no evidence of association between education or household income and lifetime risk of AF

Background:Patient-reported outcome (PRO) assessments are commonly used in clinical heart failure (HF) trials and have been shown to be valid, reliable, sensitive measures of patients’ symptoms, function and quality of life, as well as prognostic of clinical events. To be used in routine care, they also need to be interpretable to providers and patients. Patients’ perspectives on PRO collection and results communication have not been studied.Methods:We conducted a mixed methods study of 24 ambulatory adult HF patients (50% men) who completed PROs as part of care at a HF clinic. Study procedures included (1) qualitative telephone interviews and (2) quantitative surveys following interviews. We employed thematic analysis to analyze and code transcripts using an iterative coding process and descriptive statistics to analyze the survey. Qualitative findings were purposefully linked to quantitative results.Findings:Three themes in qualitative analyses were linked to the quantitative survey: 1. Utility of data: Most participants noted that PRO questionnaires were a useful tool to better understand their health if their providers discussed the results with them, and to provide additional information to help improve their treatment. Ninety-two % (22/24) of participants strongly agreed or agreed (SA/A) and 8% (2/24) were neutral that completing the questionnaires changed their care and improved their health. Ninety-six % (23/24) of participants SA/A and 4% (1/24) were neutral that completing the questionnaires would make evaluation of their well-being more accurate. 2. Length and frequency of data collection: Most participants felt that questionnaire length (13-29 questions completed in 3-8 minutes on average) and frequency of implementation (at every visit) were satisfactory. Sixty-three % (15/24) and 37% (9/24) of participants felt that maximum number of questions should be 5-15 and >15, respectively. Eighty-three % (20/24) and 17% (4/24) of participants felt that maximum time required for completion should be 5 or 10 and >10 minutes, respectively. 3. Communication with providers: Most participants noted that their providers discussed results of PRO questionnaires with them only once or not at all and participants who had this discussion with their providers felt that providers understood their responses. Sixty-two % (15/24), 21% (5/24) and 17% (4/24) of participants SA/A, were neutral and disagreed or strongly disagreed that their providers effectively discussed results of their PROs with them.Conclusions:Qualitative results provided depth and interpretability of quantitative survey results. These results indicate successful implementation and utility of PRO questionnaires in the HF clinic, while highlighting a need for more frequent discussion of PRO results between providers and patients. Further use of PROs may lead to improved cardiovascular health and prognosis in HF.

Introduction:Sociodemographic factors (SDFs) are known to influence clinical outcomes in patients treated for various diseases. To what extent SDFs affect health-related quality of life (HRQoL) in heart failure (HF) has not been fully described.Methods:HRQoL impairment was assessed in consecutive patients in a large HF clinic using patient reported outcome (PRO) instruments - the HF specific Kansas City Cardiomyopathy Questionnaire (KCCQ-12) and the generic Visual Analogue Scale (VAS); scales 0-100. We dichotomized both scales based on severity of QoL impairment: severe to very severe (0-50) and mild to moderate (51-100). The SDFs of interest were age (continuous), sex, race (white vs non-white), partnership status (partnered vs not partnered) and health insurance type (Medicare vs Medicaid vs self-pay vs commercial). We examined associations of SDFs with KCCQ-12 and VAS in univariate analyses and multivariable adjusted logistic regression models.Results:A total of 1,016 patients were included, of whom 52.3% had severe to very severe QoL limitation by KCCQ-12 and 50.6% by VAS. After adjusting for covariates including type of HF, substance abuse and a comorbidity score, health insurance was the only SDF independently associated with HRQoL. Compared to commercial insurance, patients enrolled in Medicaid (OR = 2.58; 95% CI: 1.57, 4.25) and Medicare (OR = 1.86; 95% CI: 1.31, 2.65) had higher odds of severe to very severe HF related QoL impairment as measured by KCCQ-12. Similarly, patients enrolled in Medicaid (OR = 1.72; 95% CI: 1.21, 2.44) and Medicare (OR = 1.99; 95% CI: 1.23, 3.22) had higher odds of severe to very severe general HRQoL impairment as measured by VAS.Conclusions:In a large cross-sectional sample of HF patients, health insurance type was a SDF independently associated with HRQoL. Understanding potentially modifiable factors linked to health insurance type may identify targets to improve HRQoL in HF for Medicare and Medicaid enrollees.

Hermine: AB Science: Membership on an entity's Board of Directors or advisory committees. Tamburini:Novartis pharmaceutical: Research Funding; Incyte: Research Funding.

Tamburini: Novartis pharmaceutical: Research Funding; Incyte: Research Funding.

The article reviews the music release "Doggystyle," by Snoop Doggy Dogg.