Leo Francis Buckley

Background: Prior studies on metabolite associations with incident heart failure (HF) used billing code-based definitions and lacked the data on left ventricular ejection fraction needed to determine associations with HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction.Methods: We included MGB Biobank participants who had available metabolomics data and no history of HF at baseline. The primary exposures were plasma levels of 42 metabolites measured using a H1 nuclear magnetic resonance platform. The primary outcome was incident HF, ascertained by a validated machine learning- and natural language processing-based algorithm. Multivariable Cox proportional hazards regression to quantify the associations between a 1-SD difference in metabolite level and the time to incident HF. Mendelian randomization analysis was used test the potential causality of each metabolite-HF association.Results: The final analytical cohort included 38,628 individuals with a mean age of 63 years (56% women). Higher plasma levels of glutamine associated with a higher risk of incident HF (HR [95% CI]: 1.21 [1.07-1.35]) while higher levels of DHA (0.85 [0.75-0.95]), phosphatidylcholines (0.85 [0.75-0.97]), phosphoglycerides (0.86 [0.76-0.97]) and total cholines (0.85 [0.75-0.97]) associated with a lower HF risk. DHA and total omega-3 fatty acids associated with HFpEF. Associations with HFpEF tended to be stronger than with HFrEF for several fatty acids in individuals with obesity. Mendelian randomization analysis supported causal associations between DHA and omega-3 fatty acids with HF and left ventricular mass index. Conclusions: Dysregulated omega-3 fatty acid metabolism may be causally associated with a higher risk of incident HFpEF.

This retrospective multicenter cohort study compared the safety and efficacy of low- versus high-dose colchicine in adult patients with chronic kidney disease (CKD) treated for pericarditis between August 2015 and August 2024. CKD was identified using ICD codes and confirmed by an age- and sex-adjusted estimated glomerular filtration rate (eGFR) 2 . Patients with recurrent pericarditis or prior colchicine use before admission were excluded. Patients were categorized as receiving high-dose (≥0.6 mg/day) or low-dose (<0.6 mg/day) colchicine. The primary outcomes were colchicine-related adverse effects and a composite of dose reduction or discontinuation. Secondary outcomes included symptom improvement within 72 hours, recurrent pericarditis, and pericardial tamponade within 12 months. A total of 93 patients were included (53 high-dose and 40 low-dose). Idiopathic pericarditis was the most common etiology in both groups. End-stage kidney disease (57.5% vs. 15%) and dialysis (52.5% vs. 13%) were more common in the low-dose group. High-dose colchicine was associated with more gastrointestinal adverse events (39.6% vs. 12.5%, p=0.004), a higher rate of the composite outcome of dose reduction or discontinuation (41.5% vs. 20%, p=0.043), and more frequent dose reduction alone (30.2% vs. 7.5%, p=0.009), while discontinuation rates were similar. Symptom relief, recurrent pericarditis, and pericardial tamponade were comparable between groups. Initial colchicine doses of less than 0.6 mg daily were associated with improved tolerability in patients with CKD and pericarditis.

BACKGROUND: SGLT2 (sodium-glucose cotransporter-2) inhibitors and GLP-1R (glucagon-like peptide-1 receptor) agonists reduce the risk of major adverse cardiovascular and kidney events in individuals with various cardiometabolic conditions. The long-term efficacy and safety of these therapies, especially in low- and moderate-risk populations, remain uncertain. METHODS: We conducted a biobank-scale analysis using genetic instruments derived from naturally occurring genetic variations in the genes encoding the targets of SGLT2 inhibitors (SLC5A2) and GLP-1R agonists (GLP1R) that are associated with glycated hemoglobin levels. This Mendelian randomization study utilized data from the All of Us Research Program, which includes whole genome sequencing and electronic health records of 633 547 participants. RESULTS: Higher SGLT2 inhibitor genetic instrument scores were associated with a lower risk of heart failure (odds ratio [OR], 0.97 [95% CI, 0.96–0.99]) and chronic kidney disease (OR, 0.98 [95% CI, 0.96–0.99]). Higher GLP-1R agonist genetic instrument scores were linked to reduced risks of heart failure (OR, 0.97 [95% CI, 0.96–0.99]), chronic kidney disease (OR, 0.96 [95% CI, 0.95–0.98]), and coronary artery disease (OR, 0.98 [95% CI, 0.96–0.99]). We did not detect associations between the GLP-1R agonist instrument and multiple endocrine neoplasia or medullary thyroid carcinoma. PheWAS (Phenome-Wide Association Study) identified associations between the SGLT2 inhibitor and GLP-1R agonist genetic instruments and a lower risk of diabetes, but no other phenotypes. CONCLUSIONS: This study demonstrates the utility of biobank-scale health data for pharmacology research and suggests that, if feasible to implement in routine practice, long-term, primary prevention with an SGLT2 inhibitor or GLP-1R agonist would safely lower the risk of major adverse cardiovascular and kidney events in low- to moderate-risk adults.

Background: Prior studies on metabolite associations with incident heart failure (HF) used billing code-based definitions and lacked the data on left ventricular ejection fraction needed to determine associations with HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction. Objectives: Identify potentially causal plasma metabolite associations with HFrEF and HFpEF, ascertained using a validated machine learning- and natural language processing-based algorithm, in up to 38,000 individuals. Methods: We included MGB Biobank participants who had available metabolomics data and no history of HF at baseline. The primary exposures were plasma levels of 42 metabolites measured using a H ¹ nuclear magnetic resonance platform. The primary outcome was incident HF, ascertained by a validated machine learning- and natural language processing-based algorithm. Multivariable Cox proportional hazards regression to quantify the associations between a 1-SD difference in metabolite level and the time to incident HF. Mendelian randomization analysis was used test the potential causality of each metabolite-HF association. Results: The final analytical cohort included 38,628 individuals with a mean age of 63 years (56% women). Higher plasma levels of glutamine associated with a higher risk of incident HF (HR [95% CI]: 1.21 [1.07-1.35]) while higher levels of docosahexaenoic acid (an omega-3 fatty acid) (0.85 [0.75-0.95]), phosphatidylcholines (0.85 [0.75-0.97]), phosphoglycerides (0.86 [0.76- 0.97]) and total cholines (0.85 [0.75-0.97]) associated with a lower HF risk. Docosahexaenoic acid and total omega-3 fatty acids associated with HFpEF. Associations with HFpEF tended to be stronger than with HFrEF for several fatty acids, including omega-3 fatty acids, in individuals with obesity, but not coronary artery disease or diabetes. Mendelian randomization analysis supported causal associations between higher levels of docosahexaenoic acid and omega-3 fatty acids with a higher risk of HF and greater left ventricular mass index. Conclusions: Dysregulated omega-3 fatty acid metabolism may be causally associated with a higher risk of incident HFpEF. Condensed We investigated metabolic contributors to incident heart failure (HF) in the MGB Biobank, leveraging metabolomics and a validated machine learning/NLP algorithm for HF ascertainment. Among 38,628 participants without HF at baseline, plasma levels of 42 metabolites were evaluated using multivariable Cox models and Mendelian randomization. Higher glutamine levels were associated with increased HF risk, while docosahexaenoic acid (DHA), phosphatidylcholines, phosphoglycerides, and total cholines were inversely associated. DHA and total omega-3 fatty acids were linked to HFpEF. Mendelian randomization suggested causal associations between higher DHA and omega-3 fatty acid levels and elevated HF risk, implicating dysregulated omega-3 metabolism in HF development.

The American College of Clinical Pharmacy (ACCP) first described the role and history of the pharmacist as principal investigator (PI) in 2000. An update was published in 2010, citing evidence from NIH and the ClinicalTrials.gov registry that showed an increase in the number of individuals with a Pharm.D. degree engaging in pharmacist‐directed research. The 2025 ACCP Publications Committee was charged with providing an update to the 2010 paper. Key findings include a substantial increase in the total amount of federal funding awarded to schools of pharmacy (SoP) between 2011 and 2023, a modest increase in the number of pharmacists receiving federal grants when comparing 2010 with 2024, and evidence of pharmacist leadership and engagement in Clinical and Translational Science Award networks and service on national grant review panels. It remains challenging, however, to ascertain accurate and reliable data on pharmacists serving in PI roles because of the limitations of currently available data sources. This is especially true for pharmacist PIs who receive non‐federal funding. Future opportunities include a continued emphasis on training programs to prepare pharmacists for PI roles, greater institutional support (e.g., research infrastructure, mentoring programs) for pharmacists serving in PI roles, better promotion of research career tracks to Pharm.D. students and trainees, enhanced efforts at SoP to pursue institutional training grants, and more collaborative efforts across professional organizations to advocate for pharmacist‐scientists. An urgent call to action is necessary to ensure the future growth and success of pharmacist‐directed research.

Introduction Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the risk of major adverse cardiovascular and kidney events in individuals with various cardiometabolic conditions. The long-term efficacy and safety of these therapies, especially in low- and moderate-risk populations, remain uncertain. Methods We conducted a biobank-scale analysis using genetic instruments derived from naturally occurring genetic variations in the genes encoding the targets of SGLT2 inhibitors (SLC5A2) and GLP-1R agonists (GLP1R) that associated with HbA1c levels. This Mendelian randomization study utilized data from the All of Us Research Program, which includes whole genome sequencing and electronic health records of 633,547 participants. Results Higher SGLT2 inhibitor genetic instrument scores were associated with a lower risk of heart failure (OR: 0.97, 95% CI: 0.96 to 0.99) and chronic kidney disease (OR: 0.98, 95% CI: 0.96 to 0.99). Higher GLP-1R agonist genetic instrument scores were linked to reduced risks of heart failure (OR: 0.97, 95% CI: 0.95 to 0.99), chronic kidney disease (OR: 0.96, 95% CI: 0.94 to 0.98), and coronary artery disease (OR: 0.98, 95% CI: 0.96 to 0.99). We did not detect associations between the GLP1-R agonist instrument and multiple endocrine neoplasia or medullary thyroid carcinoma. PheWAS identified associations between the SGLT2 inhibitor and GLP-1R agonist genetic instruments and a lower risk of diabetes, but no other phenotypes. Conclusions This study demonstrates the utility of biobank-scale health data for pharmacology research and suggests that, if feasible to implement in routine practice, long-term, combined primary prevention with an SGLT2 inhibitor or GLP-1R agonist would safely lower the risk of major adverse cardiovascular and kidney events in low- to moderate-risk adults.

Aims: Hepcidin regulates plasma and tissue iron levels. We studied the association of hepcidin levels with the risk of incident heart failure (HF) and cardiac dysfunction in older adults. Methods and results: We included adults from the ongoing, longitudinal Atherosclerosis Risk in Communities (ARIC) study, who were free from prevalent anaemia and HF at Visit 5 (2011–13) and had available hepcidin and covariate data. Associations of plasma hepcidin levels with overall adjudicated incident HF, HF with reduced ejection fraction (HFrEF), and HF with preserved ejection fraction (HFpEF) were assessed using multivariable Cox proportional hazards regression models. Cross-sectional associations of hepcidin with echocardiographic measures of cardiac structure and function were estimated using multivariable linear regression models. The mean age was 75 ± 5 years old, and 56% were women. In fully adjusted models, lower hepcidin levels were associated with a higher risk of overall incident HF [hazard ratio [HR] [95% confidence interval (CI) per 50% lower hepcidin]: 1.15 [1.05–1.26]; P = 0.003] and HFpEF [HR (95% CI): 1.25 (1.10–1.42); P = 0.001]. Plasma hepcidin level was not significantly associated with the risk of incident HFrEF [HR (95% CI): 1.08 (0.94–1.24); P = 0.30]. Lower hepcidin levels were associated with higher E wave (P = 0.046), higher E/e′ ratio (P = 0.002), higher left atrial volume index (P = 0.005), and higher pulmonary artery systolic pressure (P = 0.02). Conclusion: In community-dwelling older adults without anaemia, lower plasma hepcidin levels associate with a higher risk of incident HF (particularly HFpEF) and diastolic dysfunction.

Iron plays an important role in many biological functions.^1,2 Absolute iron deficiency results from a severe reduction or absence of iron stores. Functional iron deficiency occurs in the presence of adequate iron stores but insufficient iron availability (thus, it is not a true deficiency of body stores). Although most research has focused on adverse outcomes among people with iron deficiency and anemia, iron deficiency affects nonerythropoietic tissue, such as skeletal and cardiac muscle, in the absence of anemia.^1,2 Iron deficiency has been associated with restless leg syndrome, decreased physical capacity, impaired neurocognitive function, heart failure, all-cause mortality, and other adverse outcomes independent of anemia.¹