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Contemporary insights into elamipretide\u27s mitochondrial mechanism of action and therapeutic effects
No full textMitochondria are cellular hubs integral for metabolism, signaling, and survival. Mitochondrial dysfunction is centrally involved in the aging process and an expansive array of disease states. Elamipretide is a novel mitochondria-targeting peptide that is under investigation for treating several disorders related to mitochondrial dysfunction. This review summarizes recent data that expand our understanding of the mechanism of action (MOA) of elamipretide. Elamipretide is a potential first-in-class therapeutic that targets the inner mitochondrial membrane. Despite initial descriptions of elamipretide\u27s MOA involving reactive oxygen species scavenging, the last ten years have provided a significant expansion of how this peptide influences mitochondrial bioenergetics. The cardiolipin binding properties of elamipretide have been corroborated by different investigative teams with new findings about the consequences of elamipretide-cardiolipin interactions. In particular, new studies have shown elamipretide-mediated modulation of mitochondrial membrane electrostatic potentials and assembly of cardiolipin-dependent proteins that are centrally involved in mitochondrial physiology. These effects contribute to elamipretide\u27s ability to improve mitochondrial function, structure, and bioenergetics. In animal studies, elamipretide-mediated amelioration of organ dysfunction has been observed in models of cardiac and skeletal muscle myopathies as well as ocular pathologies. A number of clinical trials with elamipretide have been recently completed, and a summary of the results focusing on Barth syndrome, primary mitochondrial myopathy, and age-related macular degeneration, is also provided herein. Elamipretide continues to show promise as a potential therapy for mitochondrial disorders. New basic science advances have improved understanding of elamipretide\u27s MOA, enabling a better understanding of the molecular consequences of elamipretide-cardiolipin interactions
Characteristics and Outcomes of Older Patients Undergoing Protected Percutaneous Coronary Intervention With Impella
No full textBACKGROUND: In patients undergoing high-risk percutaneous coronary intervention, Impella has become an important adjunctive tool to support revascularization. The impact of age on the outcomes of patients undergoing high-risk percutaneous coronary intervention is limited. The aim of this study is to describe the characteristics and outcomes of patients ≥ 75 years of age undergoing Impella-supported high-risk percutaneous coronary intervention.
METHODS AND RESULTS: Baseline characteristics and outcomes of patients ≥75 years of age versus those of patients \u3c 75 years of age in patients enrolled in the cVAD PROTECT III (Catheter-Based Ventricular Assist Device Prospective, Multi-Center, Randomized Controlled Trial of the IMPELLA RECOVER LP 2.5 System Versus Intra Aortic Balloon Pump in Patients Undergoing Non Emergent High Risk Percutaneous Coronary Intervention) study (NCT04136392). Major adverse cardiovascular and cerebral events (composite of all-cause death, nonfatal myocardial infarction, stroke/transient ischemic attack, and repeat revascularization) were assessed at 30 and 90 days and all-cause death at 1 year. Out of 1237 patients, 493 (39.9%) patients were ≥75 years of age. Patients ≥ 75 years of age had less diabetes and prior myocardial infarction, more hypertension and dyslipidemia, worse renal function, more severe valvular heart disease, but higher left ventricular ejection fraction (P\u3c 0.05 for all comparisons). Baseline Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery scores were similar between groups. Older patients underwent more left main percutaneous coronary intervention (58% versus 39%; P\u3c 0.0001), atherectomy (32% versus 22%; P\u3c 0.0001), and femoral access (87% versus 79%, P=0.0003) as compared with younger patients. In-hospital vascular complications did not differ, but rates of respiratory failure, pericardial tamponade, and cardiogenic shock were higher in older patients. Rates of all-cause death and major adverse cardiovascular and cerebral events did not differ between groups at 30 and 90 days. Rates of all-cause death at 1 year were higher in patients ≥ 75 years (adjusted hazard ratio, 1.99 [95% CI, 1.24-3.18], P=0.004).
CONCLUSIONS: Impella-supported high-risk percutaneous coronary intervention in older patients is feasible with an acceptable safety profile. However, age ≥ 75 years remained a statistically significant predictor for all-cause death at 1 year.
REGISTRATION: URL: https://clinicaltrials.gov; Unique Identifier: NCT04136392
Fish and CHIP: Concurrent Percutaneous Left Ventricular Thrombus Retrieval and Complex Coronary Intervention With Hemodynamic Support
No full textGenetic Propensity for Delay Discounting and Educational Attainment in Adults Are Associated With Delay Discounting in Preadolescents: Findings From the Adolescent Brain Cognitive Development Study
No full textHigher delay discounting (DD) (i.e., propensity to devalue larger, delayed rewards over immediate, smaller rewards) is a transdiagnostic marker underpinning multiple health behaviors. Although genetic influences account for some of the variability in DD among adults, less is known about the genetic contributors to DD among preadolescents. We examined whether polygenic scores (PGS) for DD, educational attainment, and behavioral traits (i.e., impulsivity, inhibition, and externalizing behavior) were associated with phenotypic DD among preadolescents. Participants included youth (N = 8982, 53% male) from the Adolescent Brain Cognitive Development Study who completed an Adjusting Delay Discounting Task at the 1-year follow-up and had valid genetic data. PGS for DD, educational attainment, impulsivity, inhibition, and externalizing behaviors were created based on the largest GWAS available. Separate linear mixed effects models were conducted in individuals most genetically similar to European (EUR; n = 4972), African (AFR; n = 1769), and Admixed American (AMR; n = 2241) reference panels. After adjusting for age, sex, income, and the top ten genetic ancestry principal components, greater PGS for DD and lower educational attainment (but not impulsivity, inhibition, or externalizing) were associated with higher rates of DD (i.e., preference for sooner, smaller rewards) in participants most genetically similar to EUR reference panels. Findings provide insight into the influence of genetic propensity for DD and educational attainment on the discounting tendencies of preadolescents, particularly those most genetically similar to European reference samples, thereby advancing our understanding of the etiology of choice behaviors in this population
Evidence-based consensus on the clinical application of photobiomodulation
No full textBACKGROUND: There is a lack of evidence-based consensus to assist clinicians in using photobiomodulation (PBM).
OBJECTIVE: To create a consensus on the safe and effective use of PBM.
METHODS: A systematic literature review of Embase and MEDLINE was conducted in June 2022 to identify publications reporting research on PBM. An international multidisciplinary panel was convened to draft recommendations informed by the systematic search; they were refined through 2 rounds of Delphi survey, 2 consensus meetings, and iterative review by all panelists until unanimous consensus was achieved.
RESULTS: A multidisciplinary panel of experts (n = 21) was assembled based on publication history. The key findings that informed the consensus developed by the expert panel were as follows: PBM is a safe treatment modality for adult patients and red light PBM does not induce DNA damage. PBM is an effective treatment option for peripheral neuropathy, androgenic alopecia, wound ulcers due to multiple etiologies, decubitus ulcers, pain attributed to diabetic foot ulcers, and acute radiation dermatitis.
CONCLUSION: The systematic literature search and structured Delphi consensus approach culminated in an evidence-based clinical practice guideline for safe and effective use of PBM in medical and aesthetic applications. Future research will further bolster our understanding of this evolving noninvasive technique
A Case of Systemic Lupus Erythematosus Complicated by Secondary Evans Syndrome
No full textEvans syndrome (ES) is a condition that describes the development of multiple cytopenias, including autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia (AIN). ES can be idiopathic or caused by an underlying condition, known as secondary ES. While secondary ES is associated with increased morbidity and mortality, any diagnosis of ES confers a poor prognosis. In this case report, we describe a young male patient diagnosed with systemic lupus erythematosus (SLE) and secondary ES that was complicated by multiple relapses and subsequent infections, bleeding events, and thrombotic events that ultimately led to the passing of the patient
Glaucoma Patient Perspectives on Effective Coaching for Self-Management
No full textPRECIS: In semi-structured exit interviews, participants in a personalized glaucoma coaching program reported improved self-efficacy in managing their disease. Coaching was frequently cited as catalyst to enhancing medication adherence, emphasizing its role in team-based care.
PURPOSE: To assess patients\u27 experience with coaching to motivate improved adherence to glaucoma self-management.
METHODS AND MATERIALS: Participants in the Support, Educate, Empower (SEE) personalized glaucoma coaching program completed exit interviews after participating in a six-month coaching program. Interviews were audio-recorded and transcribed verbatim. Transcripts were analyzed using interpretivist grounded theory. Thematic saturation was reached after coding 30 interviews; 32 were included. Themes were identified, a codebook was generated, and two researchers coded the transcripts (NLC, DTD) and a third adjudicated any disagreements (EF). Main outcomes measures were defined as themes and the number of participants who expressed a theme.
RESULTS: Of the 32 participants interviewed in this study, 59% (n=19) identified as male, 41% (n=13) identified as female, 50% (n=16) identified as Black, 34% (n=11) identified as White, 6% (n=2) identified as Asian. Major themes surrounding coaching included how coaching promoted change in eye drop use, knowledge learned from the coach, feeling accountable to the coach, the coach being accessible, how coaches demonstrated empathy, how the coach collaborated to help people develop a sense of control and efficacy over glaucoma self-management, and how coaches built rapport. Additional themes were program satisfaction, fear of vision loss as a motivator to improve glaucoma self-management, and constructive feedback for the program.
CONCLUSION: This qualitative assessment of the SEE personalized glaucoma coaching program demonstrated that high-quality coaching and rapport building may help patients with previously low medication adherence feel more motivated and in control of their glaucoma
Medial Portal Placement for ACL Femoral Tunnel Drilling With an Over-the-Top Guide: Concepts and Technique
No full textBACKGROUND: The rate of graft failure after anterior cruciate ligament (ACL) reconstruction ranges from 3% to 22%. Surgeons must mitigate risks of failure by limiting technical errors. Femoral tunnel malposition has been cited as the most common technical error associated with ACL reconstruction. As such, techniques for femoral tunnel drilling have evolved to ensure placement of the tunnel within the anatomic footprint of the native ACL. If using an over-the-top guide, the placement of the medial portal becomes critical to ensure safe and accurate drilling.
INDICATIONS: The purpose of this video is to highlight key concepts related to the proper placement of the medial portal during ACL reconstruction when using an over-the-top guide and low-profile reamer.
TECHNIQUE DESCRIPTION: A skin marking for the planned medial portal is made approximately 1.5 to 2 cm medial to the patellar tendon while palpating the joint line. After standard bone-patella tendon-bone (BTB) autograft harvest and anterolateral portal establishment, the medial portal is created under direct visualization, utilizing an 18-gauge spinal needle to ensure proper trajectory for over-the-top femoral tunnel drilling. After the tibial tunnel is prepared, the over-the-top guide is inserted via the medial portal and hooked onto the back wall. The knee is then hyperflexed and the beath pin is advanced out the lateral thigh. The low-profile reamer is advanced over the wire and reamed to the desired tunnel depth. The back wall integrity is confirmed and the prepared autograft is then passed and secured via interference screw fixation.
RESULTS: This technique provides a consistent and reproducible method of femoral tunnel placement in the anatomic footprint of the ACL without damaging the medial femoral condyle. We can also instrument through the same portal to treat meniscal pathology without necessitating an accessory medial portal.
DISCUSSION/CONCLUSION: Appropriate medial portal placement for femoral tunnel drilling with an over-the-top guide is critical for safe, reproducible, and consistent tunnel location.
PATIENT CONSENT DISCLOSURE STATEMENT: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication
Identification of 2 novel noncoding variants in patients with Diamond-Blackfan anemia syndrome by whole genome sequencing
No full textDiamond-Blackfan anemia syndrome (DBAS) is a rare congenital disorder with variable penetrance and expressivity and is characterized by pure red cell aplasia that typically manifests as early-onset chronic macrocytic or normocytic anemia and is often associated with other congenital anomalies. DBAS is etiologically heterogeneous with \u3e20 known DBAS-associated genes that encode small and large ribosomal protein subunits and an inheritance pattern that is largely autosomal dominant or sporadic. We report 2 DBAS cases with previous negative genetic testing, which included targeted gene panels, karyotype analysis, chromosome breakage analysis, and whole exome sequencing. Although clinical whole genome sequencing (WGS) was initially negative, in-depth reanalysis identified 2 novel noncoding variants in the RPS gene family, namely a maternally inherited splicing variant at the end of the first noncoding exon in RPS7 (NM_001011.4, c.-19G\u3eC) in family 1 and a deep intronic de novo variant in RPS19 (NM_001022.4, c.172+350C\u3eT) in family 2. In family 1, several maternal relatives were identified who shared the same variant through cascade testing; clinically, they exhibited variable degrees of anemia and elevated erythrocyte adenosine deaminase activity, a marker for DBAS. RNA sequencing analysis demonstrated deleterious functional consequences for both noncoding variants. In case 1, hematopoietic stem cell transplant with an unaffected matched sibling donor who did not carry the variant successfully cured the congenital anemia. This study identified novel noncoding variants and underscores the clinical utility of WGS in accelerating diagnosis and improving care for rare genetic disorders, particularly when timely treatment decisions are critically important
Accuracy of self-reported exam indications for breast cancer screening
No full textWe validated updated National Health Interview Survey questions on mammography indications compared with electronic health records (EHRs). We asked 244 Kaiser Permanente Washington members ages 40-74 years and eligible for breast cancer screening to self-report their most recent mammogram reason by using a series of new hierarchical yes/no questions. We first asked if they had the mammogram because of a health problem, then as a follow-up test, and last for screening. We compared self-reported reasons with 2 EHR datasets: procedure/diagnostic codes and radiologist-defined indications. Self-reported exams for a health problem had 89.2% agreement with codes and 92.2% agreement with radiologist-defined indications. Self-reported exams for follow-up had 87.5% agreement with codes and 89.3% agreement with radiologist-defined indications. Self-reported exams for screening had 91.4% agreement with codes and 95.7% agreement with radiologist-defined indications. Self-reported mammogram indications have good agreement with procedure/diagnostic codes and radiologist-reported indications, when asked using this novel hierarchical approach