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During replication, human mitochondrial DNA (mtDNA) takes on a triple-stranded structure known as a D-loop, which is implicated in replication and transcription. 1-Methyl-4-phenylpyridinium ion (MPP[sup +]), a toxin inducing parkinsonism, inhibits mtDNA replication, possibly by resolving the D-loops. For initiation of mtDNA replication, mitochondria are thought to have another triple-stranded structure, an R-loop. The R-loop, which is resolved by a bacterial junction-specific helicase, RecG, is also resolved by MPP[sup +]. Because mitochondrial D-loops are likewise resolved by RecG, the D- and R-loops may share a similar branched structure. MPP[sup +] resolves cruciform DNA in supercoiled DNA. MPP[sup +] converts a stacked conformation to an extended conformation in a synthetic Holliday junction. This conversion is reversed by 1 mM Mg[sup 2+], as is the resolution of the D-loops or cruciform DNA. These observations suggest that the junction structure of mitochondrial D- and R-loops is affected by MPP[sup +]. [ABSTRACT FROM AUTHOR]

Acute kidney dysfunction is commonly encountered in patients with advanced heart failure (HF), and it carries significant prognostic implications, often leading to poorer outcomes and increased mortality rates. It can alter the course of decision making for left ventricular assist device (LVAD) and cardiac transplantation candidacy. Kidney replacement therapies (KRTs) offer a critical intervention in this context but require careful consideration of timing, various types of KRT modalities and individual patients' preferences and circumstances. This review discusses the intricacies of KRT in advanced HF, examining how to optimize timing and choose among the various KRT modalities. It also provides a detailed discussion of the unique clinical scenarios that clinicians may face when treating this vulnerable patient group., Competing Interests: Disclosures WHWT serves as consultant to Sequana Medical, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics, Boston Scientific, WhiteSwell, CardiaTec Biosciences, Intellia Therapeutics, Bristol Myers Squibb, Alleviant Medical, Alexion Pharmaceuticals, and Salubris Biotherapeutics and has received honoraria from Springer, Belvoir Media Group, and American Board of Internal Medicine. SD and Cleveland Clinic Innovations Center hold a U.S. patent for predictive models for CS-AKI, and SD reports receiving speaker fees from Outset Medical, Baxter, BioMerieux and Astute Medical outside the submitted work. All other authors have no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Healthcare coverage has been shown to have implications in the prevalence of coronary artery disease. We explore the impact of lack of healthcare coverage on ischemic heart disease (IHD) mortality in the US., Methods: We obtained county-level IHD mortality and healthcare coverage data from the CDC databases for a total of 3,119 US counties. The age-adjusted prevalence of current lack of health insurance among individuals aged 18 to 64 years were obtained for the years 2018 and 2019 and were placed into four quartiles. First (Q1) and fourth quartile (Q4) had the least and highest age-adjusted prevalence of adults without health insurance, respectively. IHD mortality rates, adjusted for age through the direct method, were obtained for the same years and compared among quartiles. Ordinary least squares (OLS) regression for each demographic variable was conducted with the quartiles as an ordinal predictor variable and the age-adjusted mortality rate as the outcome variable., Results: We identified a total of 172,942 deaths related to ischemic heart disease between 2018 and 2019. Overall AAMR was higher in Q4 (92.79 [95% CI, 92.35-93.23]) compared to Q1 (83.14 [95% CI, 82.74-83.54]), accounting for 9.65 excess deaths per 100,000 person-years (slope = 3.47, p = 0.09). Mortality rates in Q4 for males (126.20 [95% CI, 125.42-126.98] and females (65.57 [95% CI, 65.08-66.05]) were higher compared to Q1 (115.72 [95% CI, 114.99-116.44] and 57.48 [95% CI, 57.04-57.91], respectively), accounting for 10.48 and 8.09 excess deaths per 100,000 person-years for males and females, respectively. Similar trends were seen among Hispanic and non-Hispanic populations. Northeastern, Southern, and Western regions had higher AAMR within Q4 compared to Q1, with higher prevalence of current lack of health insurance accounting for 49.2, 8.15, and 29.04 excess deaths per 100,000 person-years, respectively., Conclusion: A higher prevalence of adults without healthcare coverage may be associated with increased IHD mortality rates. Our results serve as a hypothesis-generating platform for future research in this area., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ibrahim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Cardiovascular disease is a leading cause of morbidity and mortality, largely dominated by ischemic heart diseases (IHDs). Social determinants of health, including geographic, psychosocial, and socioeconomic factors, influence the development of IHD., Objectives: This study aimed to evaluate yearly trends and disparities in IHD mortality and to assess the impact of social vulnerability., Methods: We performed cross-sectional analyses using United States county-level mortality data and social vulnerability index (SVI) obtained from the Centers for Disease Control and Prevention databases. Age-adjusted mortality rates (AAMRs) per 100,000 population were compared between aggregated U.S. county groups, stratified by demographic information and SVI quartiles. Log-linear regression models were used to identify mortality trends from 1999 to 2020, with inflection points determined through the Monte-Carlo permutation test., Results: We identified a total of 9,108,644 deaths related to IHD between 1999 and 2020. Overall AAMR decreased from 194.6 in 1999 to 91.8 in 2020. Males (AAMR: 161.51) and Black (AAMR: 141.49) populations exhibited higher AAMR compared to females (AAMR: 93.16) and White (AAMR: 123.34) populations, respectively. Disproportionate AAMRs were observed among nonmetropolitan (AAMR: 136.17) and Northeastern (AAMR: 132.96) regions. Counties with a higher SVI experienced a greater AAMR, with a cumulative excess of 20.91 deaths per 100,000 person-years associated with increased social vulnerability., Conclusions: Despite a decline in IHD mortality from 1999 to 2020, disparities persisted among racial, gender, and geographic subgroups. A higher SVI was linked to increased IHD mortality. Policy interventions should prioritize integrating the SVI into health care delivery systems to effectively address these disparities., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN PATIENT CARE: Through our cross-sectional analyses, we discovered that Black and male populations faced the highest risk of mortality associated with ischemic heart diseases. Moreover, our findings revealed that residents residing in U.S. counties characterized by higher social vulnerability experienced worse mortality outcomes related to ischemic heart disease. These insights highlight the need for targeted interventions and tailored patient care strategies to address the specific risks and challenges faced by these vulnerable populations. TRANSLATIONAL OUTLOOK: It is crucial to incorporate demographic details and the social vulnerability index within health care delivery systems and risk algorithms. This integration will enable the identification of populations at a higher risk of adverse outcomes related to ischemic heart disease., (© 2023 The Authors.)

Competing Interests: Funding Support and Author Disclosures Dr Seckeler has received funding support from PANDA (People Acting Now Discover Answers) for the University of Arizona Congenital Cardiac 3D Printing Program. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Omecamtiv mecarbil (OM) is a direct myosin activator that augments left ventricular systolic function. This review compares OM to placebo by evaluating its effect on clinical outcomes and adverse events in patients with heart failure with reduced left ventricular ejection fraction., Methods and Results: A literature search of multiple databases for randomized controlled trials (RCTs) investigating OM versus placebo was undertaken. Six RCTs comprising 9596 patients were included. Use of OM was associated with a reduced risk of stroke (RR: 0.69; 95% CI 0.52-0.92). There was no significant mean difference (MD) change in the KCCQ total symptom score (MD: 1.82, 95% CI - 1.33 to 4.97), all-cause death (RR: 1.00; 95% CI 0.93-1.07), hospital readmissions (RR: 0.96; 95% CI 0.90-1.03), myocardial infarction (RR: 1.05; 95% CI 0.83-1.33), cardiovascular death (RR: 1.01; 95% CI 0.92-1.10), heart failure (HF) events (RR: 0.95; 95% CI 0.89-1.02), or a composite of cardiovascular death or HF events (RR: 0.97; 95% CI 0.93-1.02). In addition, OM was associated with an increased risk of dizziness (RR: 1.25; 95% CI 1.04-1.50) and hypotension (RR: 1.17; 95% CI 1.01-1.36). Other adverse events including ventricular tachyarrhythmias, (RR: 0.95; 95% CI 0.82-1.11), supraventricular tachyarrhythmias and atrial fibrillation/flutter (RR: 0.73; 95% CI 0.46-1.18), dyspnea (RR: 1.00; 95% CI 0.86-1.18), and acute renal injury (RR: 0.88; 95% CI 0.60-1.27) were not significant., Conclusion: OM is generally well tolerated. We identified a reduced risk of stroke with use of OM. However, there was no improvement in other clinical outcomes or quality of life. Study protocol was registered in PROSPERO international prospective register of systematic reviews (CRD42022348423)., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Competing Interests: None. The author has no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. No disclosures.

Before surgery and other invasive treatments, decisions must be made on whether to discontinue drugs and provide appropriate drug holidays especially for antithrombotic drugs, and this is made difficult by the large number of available drugs and associated guidelines. We have therefore developed an online application for perioperative drug discontinuation and resumption management, named Saga Application for Management of Drug Holidays in PeriOperative Periods (SAMPOP).Multidisciplinary medical staff at Saga University Hospital (SUH) worked together to build an evidence-based Perioperative Drug Discontinuation Management Database (PDDMD) and developed the user-friendly SAMPOP online application via preliminary verification at SUH. From September 2018 to February 2020, 420 medical staff at SUH, including physicians, nurses, and pharmacists, installed and tested SAMPOP.Rate per surgical procedure for forgetting to discontinue antithrombotic drugs preoperatively decreased from 0.18% to 0.09% as of August 2019, 12 months after the introduction of SAMPOP (P = .1359). In addition, six months later, it decreased further to 0.03% as of February 2020 (P = .0436). Forgetting to resume antithrombotic drugs postoperatively decreased from 0.20% to 0.02% as of August 2019, 12 months after the introduction of SAMPOP (P = .0008). There was no case of forgetting to resume the medication in the last 6 months.SAMPOP may be useful for management of drug holidays in the clinic and warrants further evaluation of its safety and efficacy.

Robotically-assisted surgery using da Vinci® surgical system is a challenging technology as a minimally- invasive operation. However, few Japanese institutions employ robotic surgery for procedures involving the upper intestinal tract because its advantages have not been fully established. Robotic gastrectomy requires more complicated devices and procedures than con- ventional laparoscopic surgery. For example, da Vinci® system covers the patient's upper body during the operation, and anesthesiologists are forced to be far away from the head. This is a disadvantage for airway management, especially during emergency situation. Thus, all procedures and potential risk factors should be simulated and planned before the operation. In addi- tion to their role in anesthetic management, anesthesi- ologists are expected to play important roles as coordinators of the medical staffs during surgery.

According to a survey of anesthesia-related critical incidents by the Japanese Society of Anesthesiologists, hemorrhage was the major cause of cardiac arrest developing in the operating room. To deal with critical hemorrhage swiftly, not only cooperation between anesthesiologists and surgeons but also the linkage of operating rooms with transfusion management divisions and the blood center is important. It is desirable for the hospital transfusion committee to prepare hospital regulations on 'actions to be taken to manage critical hemorrhage', and practice the implementation of these guidelines by simulated drills. When critical hemorrhage occurs, a person in charge is appointed, and an emergency is declared (call for manpower and notification of the emergency to the transfusion management divisions). A person in charge comprehensively assesses the hemostatic condition, hemodynamics, laboratory data, and blood product supply system, and consults the operator regarding the continuation of surgery or changing surgical procedures. When time is short, the cross-matching test is omitted, and the ABO-identical blood is used. When a supply of the identical ABO-type blood is not available, compatible blood type is used. The evolving concept of hemostatic resuscitation seems to be important to prevent coagulopathy, which easily develops during massive hemorrhage. Anesthesiologists should be aware of the risk of such an emergency transfusion and procedures to be taken to switch to transfusion of the ABO-identical blood. Establishment of a hospital emergency transfusion system depends on the overall capability of the critical and crisis management systems of the hospital.

It is known that mitochondrial DNA (mtDNA) replication is independent of the cell cycle. Even in post-mitotic cells in which nuclear DNA replication has ceased, mtDNA is believed to still be replicating. Here, we investigated the turnover rate of mtDNA in primary rat hepatocytes, which are quiescent cells. Southwestern blot analysis using 5-bromo-2'-deoxyuridine (BrdU) was employed to estimate the activity of full-length mtDNA replication and to determine efficient doses of replication inhibitors. Southern blot analysis showed that a two-day treatment with 20mM 2',3'-dideoxycytidine and 0.2mug/ml ethidium bromide caused a 37% reduction in the amount of mtDNA, indicating that the hepatocytes had a considerably high rate of turnover of mtDNA. Further, pulse-chase analysis using Southwestern analysis showed that the amount of newly synthesized mtDNA labeled with BrdU declined to 60% of the basal level within two days. Because the rate of reduction of the new mtDNA was very similar to the overall turnover rate described above, it appears that degrading mtDNA molecules were randomly chosen. Thus, we demonstrated that there is highly active and random turnover of mtDNA in hepatocytes.

During replication, mitochondrial DNA (mtDNA) takes on a triple-stranded structure called a D-loop. Although their physiological roles are not understood, D-loops are implicated in replication and transcription of mtDNA. Little is known about the turnover of D-loops. We investigated the effects of mitochondrial transcription factor A (TFAM) and single-stranded DNA-binding protein (mtSSB) on D-loops. In human HeLa cells, TFAM and mtSSB are, respectively, 1700- and 3000-fold more abundant than mtDNA. This level of TFAM is two orders of magnitude higher than reported previously and is sufficient to wrap human mtDNA entirely. TFAM resolves D-loops in vitro if added in similar stoichiometries. mtSSB inhibits the resolution of mtDNA by TFAM but enhances resolution by RecG, a junction-specific helicase from Escherichia coli. Hence, mtSSB functions in both stabilization and resolution. We propose that TFAM and mtSSB are cooperatively involved in stabilizing D-loops and in the maintenance of mtDNA.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine has been reported to cause parkinsonism via its neurotoxic form, 1-methyl-4-phenylpyridinium ion (MPP+), which inhibits complex I of the mitochondrial respiratory chain. Its parkinsonism-causing mechanisms attract a great deal of interest as a model of the disease. Recently, we reported that MPP+ strongly decreases the amount of mtDNA independent of the inhibition of complex I. Maintenance of a proper amount of mtDNA is essential for the normal function of mitochondria as exemplified in many mitochondrial diseases. The most characteristic feature in vertebral mtDNA replication is that H-strand synthesis proceeds displacing the parental H-strand as a long single strand. It forms the D-loop, a triplex replication intermediate composed of the parental L-strand, nascent H-strand and displaced H-strand. Here we show that MPP+ does not inhibit DNA synthesis by DNA polymerase gamma, but rather releases the nascent H-strands from mtDNA both in organello and in vitro. This indicates that MPP+ directly destabilizes the D-loop structure, thereby inhibiting replication. This study raises a new mechanism, i.e. destabilization of replication intermediates, for depletion of mtDNA.