OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling

Autosomal Dominant Optic Atrophy (ADOA), a disease that causes blindness and other neurological disorders, is linked to OPA1 mutations. OPA1, dependent on its GTPase and GED domains, governs inner mitochondrial membrane (IMM) fusion and cristae organization, which are central to oxidative metabolism. Mitochondrial dynamics and IMM organization have also been implicated in Ca2+ homeostasis and signaling but the specific involvements of OPA1 in Ca2+ dynamics remain to be established. Here we studied the possible outcomes of OPA1 and its ADOA-linked mutations in Ca2+ homeostasis using rescue and overexpression strategies in Opa1-deficient and wild-type murine embryonic fibroblasts (MEFs), respectively and in human ADOA-derived fibroblasts. MEFs lacking Opa1 required less Ca2+ mobilization from the endoplasmic reticulum (ER) to induce a mitochondrial matrix [Ca2+] rise ([Ca2+]mito). This was associated with closer ER-mitochondria contacts and no significant changes in the mitochondrial calcium uniporter complex. Patient cells carrying OPA1 GTPase or GED domain mutations also exhibited altered Ca2+ homeostasis, and the mutations associated with lower OPA1 levels displayed closer ER-mitochondria gaps. Furthermore, in Opa1−/− MEF background, we found that acute expression of OPA1 GTPase mutants but no GED mutants, partially restored cytosolic [Ca2+] ([Ca2+]cyto) needed for a prompt [Ca2+]mito rise. Finally, OPA1 mutants’ overexpression in WT MEFs disrupted Ca2+ homeostasis, partially recapitulating the observations in ADOA patient cells. Thus, OPA1 modulates functional ER-mitochondria coupling likely through the OPA1 GED domain in Opa1−/− MEFs. However, the co-existence of WT and mutant forms of OPA1 in patients promotes an imbalance of Ca2+ homeostasis without a domain-specific effect, likely contributing to the overall ADOA progress.

Claims-Based Network Analysis of Disease Progressions in Complex and Non-Complex Older Adults

Older adults are the fastest growing subset of complex patients with high medical, behavioral, and social needs. Understanding differences in disease progression patterns between complex and non-complex older adults is critical for understanding disease risk and tailoring patient-centered interventions. We identified complex patients as those having frequent medical encounters and multiple chronic conditions within the first year of the study period and non-complex patients as the converse. This study compares the disease progression patterns of (a) complex and (b) non-complex older adults by creating disease progression networks (DPN) from claims data of 762,362 patients (mean age = 73) from 2016 to 2020. We characterized the network size and density between the complex patient DPN (C-DPN) and non-complex patient DPN (NC-DPN), and compared disease progression incidence, time-to-progression, and age- and gender-related risk. Results show that the C-DPN was denser and had a wider range of values for risk of progression compared to the NC-DPN. This implies more varied disease progression patterns occurring in the complex adults. We were also able to compare (median) time-to-progressions of diseases relative to each subpopulation and found variation in disease progression time. Furthermore, k-means clustering on the network allowed us to identify highly connected diseases involved in many disease pathways that are prevalent among older adults. (e.g., lipoprotein disorders, hypertension, major depressive disorder). Our results suggest that DPNs can be used to identify important conditions and time-points for tailoring care to the complex and non-complex older adults.

Medical Students' Perceptions of Patient-Doctor Relationship in South Korea: Concept Mapping Analysis

Introduction: The patient-doctor relationship has evolved from early paternalism to a consumerism and partnership model that emphasizes cooperation. Patient-doctor relationships might vary with the socio-cultural environment, because the medical environment affects such relationships.Method: We investigated the patient-doctor relationship among medical students through concept mapping analysis. Twenty-six fourth-grade Korean medical students wrote a reflection journal and participated in the concept classification and the importance evaluation of the derived concept. ALSCAL multidimensional scaling and Ward hierarchical cluster analysis were performed. Also, the 5-point Likert scale was used to evaluate the importance of the concept.Results: Sixty-six statements about the patient-doctor relationship were extracted and grouped into six clusters. The x-axis is the dimension of “Information-Respect,” and the y-axis is “Changeability-Persistence.” Six patient-doctor concepts were derived and students evaluated “Patient-centered” as the most important.Conclusions: Medical students express various concepts of the patient-doctor relationship. Considering that they may encounter various medical conditions and patients, it is necessary that they understand deeply the complex patient-doctor relationship.

Pulmonary Embolism Response Team (PERT) – A New Paradigm for the Treatment of Pulmonary Embolism

: Pulmonary embolism (PE) is the third leading cause of cardiovascular mortality. Patients with PE can present with a wide array of symptoms, ranging from mild to life threatening. The mainstay of PE treatment is anticoagulation; however, there are many advanced options available for more severe patients, including catheter-directed interventions, surgical treatments, and hemodynamic support. Although different risk scores and clinical guidelines exist, the primary treating teams are frequently left uncertain on the most suitable treatment for a specific complex patient. Pulmonary Embolism Response Teams (PERT), composed of multidisciplinary experts, have emerged and been implemented in many centers and are available 24 hours a day to help guide the primary team. PERTs have changed the way complex PE patients are managed. In centers with a PERT, teams are called upon very frequently and there is a significant increase in the use of advanced treatments for PE, although there are differences between centers based upon the center's specific PERT protocol and available capabilities. As PE is an evolving area, and more studies are necessary, PERTs around the world can help advance the field and improve the treatment offered to PE patients.