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Cell Reports Jun 2024ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1...
ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR) macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1 tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.
PubMed: 38935501
DOI: 10.1016/j.celrep.2024.114400 -
Cell Reports Jun 2024Oligodendrocyte death is common in aging and neurodegenerative disease. In these conditions, dying oligodendrocytes must be efficiently removed to allow remyelination...
Oligodendrocyte death is common in aging and neurodegenerative disease. In these conditions, dying oligodendrocytes must be efficiently removed to allow remyelination and to prevent a feedforward degenerative cascade. Removal of this cellular debris is thought to primarily be carried out by resident microglia. To investigate the cellular dynamics underlying how microglia do this, we use a single-cell cortical demyelination model combined with longitudinal intravital imaging of dual-labeled transgenic mice. Following phagocytosis, single microglia clear the targeted oligodendrocyte and its myelin sheaths in one day via a precise, rapid, and stereotyped sequence. Deletion of the fractalkine receptor, CX3CR1, delays the microglial phagocytosis of the cell soma but has no effect on clearance of myelin sheaths. Unexpectedly, deletion of the phosphatidylserine receptor, MERTK, has no effect on oligodendrocyte or myelin sheath clearance. Thus, separate molecular signals are used to detect, engage, and clear distinct sub-compartments of dying oligodendrocytes to maintain tissue homeostasis.
PubMed: 38935500
DOI: 10.1016/j.celrep.2024.114385 -
JAMA Network Open Jun 2024The overutilization of antibiotics in very preterm infants (VPIs) at low risk of early-onset sepsis (EOS) is associated with increased mortality and morbidities....
IMPORTANCE
The overutilization of antibiotics in very preterm infants (VPIs) at low risk of early-onset sepsis (EOS) is associated with increased mortality and morbidities. Nevertheless, the association of early antibiotic exposure with bronchopulmonary dysplasia (BPD) remains equivocal.
OBJECTIVE
To evaluate the association of varying durations and types of early antibiotic exposure with the incidence of BPD in VPIs at low risk of EOS.
DESIGN, SETTING, AND PARTICIPANTS
This national multicenter cohort study utilized data from the Chinese Neonatal Network (CHNN) which prospectively collected data from January 1, 2019, to December 31, 2021. VPIs less than 32 weeks' gestational age or with birth weight less than 1500 g at low risk of EOS, defined as those born via cesarean delivery, without labor or rupture of membranes, and no clinical evidence of chorioamnionitis, were included. Data analysis was conducted from October 2022 to December 2023.
EXPOSURE
Early antibiotic exposure was defined as the total number of calendar days antibiotics were administered within the first week of life, which were further categorized as no exposure, 1 to 4 days of exposure, and 5 to 7 days of exposure.
MAIN OUTCOMES AND MEASURES
The primary outcome was the composite of moderate to severe BPD or mortality at 36 weeks' post menstrual age (PMA). Logistic regression was employed to assess factors associated with BPD or mortality using 2 different models.
RESULTS
Of the 27 176 VPIs included in the CHNN during the study period (14 874 male [54.7%] and 12 302 female [45.3%]), 6510 (23.9%; 3373 male [51.8%] and 3137 female [48.2.%]) were categorized as low risk for EOS. Among them, 1324 (20.3%) had no antibiotic exposure, 1134 (17.4%) received 1 to 4 days of antibiotics treatment, and 4052 (62.2%) received 5 to 7 days of antibiotics treatment. Of the 5186 VPIs who received antibiotics, 4098 (79.0%) received broad-spectrum antibiotics, 888 (17.1%) received narrow-spectrum antibiotics, and 200 (3.9%) received antifungals or other antibiotics. Prolonged exposure (5-7 days) was associated with increased likelihood of moderate to severe BPD or death (adjusted odds ratio [aOR], 1.23; 95% CI, 1.01-1.50). The use of broad-spectrum antibiotics (1-7 days) was also associated with a higher risk of moderate to severe BPD or death (aOR, 1.27; 95% CI, 1.04-1.55).
CONCLUSIONS AND RELEVANCE
In this cohort study of VPIs at low risk for EOS, exposure to prolonged or broad-spectrum antibiotics was associated with increased risk of developing moderate to severe BPD or mortality. These findings suggest that VPIs exposed to prolonged or broad-spectrum antibiotics early in life should be monitored for adverse outcomes.
Topics: Humans; Bronchopulmonary Dysplasia; Anti-Bacterial Agents; Infant, Newborn; Female; Male; Infant, Premature; Sepsis; China; Cohort Studies; Risk Factors; Incidence; Gestational Age; Infant, Very Low Birth Weight
PubMed: 38935376
DOI: 10.1001/jamanetworkopen.2024.18831 -
JAMA Network Open Jun 2024The US has the highest maternal mortality rate among developed countries. The Centers for Disease Control and Prevention deems nearly all of these deaths preventable,... (Observational Study)
Observational Study
IMPORTANCE
The US has the highest maternal mortality rate among developed countries. The Centers for Disease Control and Prevention deems nearly all of these deaths preventable, especially those attributable to mental health conditions. Coordination between US health care and social service systems could help further characterize circumstances and risks associated with perinatal suicide mortality.
OBJECTIVE
To examine contextual and individual precipitating circumstances and risks associated with perinatal suicide.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional observational study used a convergent mixed methods design to explore factors contributing to maternal suicides and deaths of undetermined intent (hereinafter, undetermined deaths) identified in National Violent Death Reporting System (NVDRS) data for January 1, 2003, to December 31, 2021. Analyses included decedents who were aged 10 to 50 years and pregnant or post partum at death (collectively, the perinatal group) and demographically matched female decedents who were not pregnant or recently pregnant (nonperinatal group) at death. Analyses were performed between December 2022 and December 2023.
EXPOSURES
Pregnancy status at death (perinatal or nonperinatal).
MAIN OUTCOMES AND MEASURES
The main outcomes included contributing circumstances associated with suicides and undetermined deaths cited in coroner, medical examiner, or law enforcement case narratives. The study examined quantitative differences between groups using a matched analysis and characterized key themes of salient suicide circumstances using qualitative content analysis.
RESULTS
This study included 1150 perinatal decedents identified in the NVDRS: 456 (39.6%) were pregnant at death, 203 (17.7%) were pregnant within 42 days of death, and 491 (42.7%) were pregnant within 43 to 365 days before death, yielding 694 postpartum decedents. The nonperinatal comparison group included 17 655 female decedents aged 10 to 50 years. The mean (SD) age was 29.1 (7.4) years for perinatal decedents and 35.8 (10.8) years for nonperinatal decedents. Compared with matched nonperinatal decedents, perinatal decedents had higher odds of the following identified contributing circumstances: intimate partner problems (IPPs) (odds ratio [OR], 1.45 [95% CI, 1.23-1.72]), recent argument (OR, 1.33 [95% CI, 1.09-1.61]), depressed mood (OR, 1.39 [95% CI, 1.19-1.63]), substance abuse or other abuse (OR, 1.21 [95% CI, 1.03-1.42]), physical health problems (OR, 1.37 [95% CI, 1.09-1.72]), and death of a family member or friend (OR, 1.47 [95% CI, 1.06-2.02]). The findings of the qualitative analysis emphasized the importance of mental health and identified 128 decedents (12.4%) with postpartum depression.
CONCLUSIONS AND RELEVANCE
This study provides insights into complex factors surrounding maternal suicide, and it highlights opportunities for further research to understand long-term consequences of perinatal mental health. These findings also underscore the need for targeted evidence-based interventions and effective policies targeting mental health, substance use, and IPPs to prevent maternal suicide and enhance maternal health outcomes.
Topics: Humans; Female; Pregnancy; Cross-Sectional Studies; Adult; Suicide; United States; Adolescent; Middle Aged; Young Adult; Child; Risk Factors; Maternal Mortality; Perinatal Mortality
PubMed: 38935375
DOI: 10.1001/jamanetworkopen.2024.18887 -
Health & Justice Jun 2024People incarcerated in jails are highly impacted by the opioid epidemic, and overdose education and naloxone distribution (OEND) is an effective strategy to reduce...
BACKGROUND
People incarcerated in jails are highly impacted by the opioid epidemic, and overdose education and naloxone distribution (OEND) is an effective strategy to reduce opioid overdose deaths. This study examines barriers and facilitators of fast-track OEND implementation within the jails in the Wave 1 Kentucky counties of the HEALing Communities Study during the COVID-19 pandemic.
METHODS
Meeting minutes with jail stakeholders were qualitatively coded using the Practical, Robust Implementation and Sustainability Model (PRISM) as the coding framework. The analysis highlighted the top barriers and facilitators to fast-track OEND implementation within the PRISM framework.
RESULTS
Space and staffing shortages related to the COVID-19 pandemic, disruptions in interorganizational programming from pandemic-related service suspensions, and a lack of technological solutions (e.g., reliable Internet access) for socially distanced delivery were the top barriers to fast-track OEND implementation. In addition, there were limitations on non-jail staff access to jails during COVID-19. Top facilitators included jail leadership support, the option to prioritize high-risk groups, and the incorporation of OEND processes into existing communications and management software. While the COVID-19 pandemic strained jail infrastructure, jail and partner agency collaboration led to creative implementation strategies for the successful integration of OEND into jail operations. Urban jails were more likely than rural jails to be early adopters of OEND during the public health emergency.
CONCLUSIONS
Understanding the barriers to and facilitators of OEND within jails will improve implementation efforts seeking to curb opioid overdose deaths. Jail leadership support and interorganizational efforts were key facilitators to implementation; therefore, it is recommended to increase buy-in with multiple agencies to promote success. Challenges brought on by COVID-19 have resulted in a need for innovative solutions for implementation.
CLINICAL TRIAL INFORMATION
ClinicalTrials.gov, NCT04111939, Submitted 30 September 2019, https://clinicaltrials.gov/study/NCT04111939?titles=HEALing%20Communities%20Study&rank=1 .
PubMed: 38935213
DOI: 10.1186/s40352-024-00283-8 -
Journal of the American Heart... Jun 2024Dual antiplatelet therapy (DAPT) reduces ischemic events but increases bleeding risk, especially in patients with high bleeding risk (HBR). This study aimed to compare...
Abbreviated Versus Standard Dual Antiplatelet Therapy Times After Percutaneous Coronary Intervention in Patients With High Bleeding Risk With Acute Coronary Syndrome: Insights From the SWEDEHEART Registry.
BACKGROUND
Dual antiplatelet therapy (DAPT) reduces ischemic events but increases bleeding risk, especially in patients with high bleeding risk (HBR). This study aimed to compare outcomes of abbreviated versus standard DAPT strategies in patients with HBR with acute coronary syndrome undergoing percutaneous coronary intervention.
METHODS AND RESULTS
Patients from the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-Based Bare in Heart Disease Evaluated According to Recommended Therapies) registry with at least 1 HBR criterion who underwent percutaneous coronary intervention for acute coronary syndrome were identified and included. Patients were divided into 2 groups based on their planned DAPT time at discharge: 12-month DAPT or an abbreviated DAPT strategy and matched according to their prescribed P2Y12 inhibitor at discharge. The primary outcome assessed was time to net adverse clinical events at 1 year, which encompassed cardiac death, myocardial infarction, ischemic stroke, or clinically significant bleeding. Time to major adverse cardiovascular events and the individual components of net adverse clinical events were considered secondary end points. A total of 4583 patients were included in each group. The most frequently met HBR criteria was age older than 75 years (65.6%) and Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy score ≥25 (44.6%) in the standard DAPT group and oral anticoagulant therapy (79.6%) and age 75 years and older (55.2%) in the abbreviated DAPT group. There was no statistically significant difference in net adverse clinical events (12.9% versus 13.1%; hazard ratio [HR], 0.99 [95% CI, 0.88-1.11], =0.83), major adverse cardiovascular events (8.6% versus 7.9%; HR, 1.08 [95% CI, 0.94-1.25]), or their components between groups. The results were consistent among all of the investigated subgroups.
CONCLUSIONS
In patients with HBR undergoing percutaneous coronary intervention due to acute coronary syndrome, abbreviated DAPT was associated with comparable rates of net adverse clinical events and major adverse cardiovascular events to a DAPT duration of 12 months.
PubMed: 38934886
DOI: 10.1161/JAHA.124.034709 -
Journal of the American Heart... Jun 2024While significant progress has been made in reducing disparities within the US health care system, notable gaps remain. This article explores existing disparities within... (Review)
Review
While significant progress has been made in reducing disparities within the US health care system, notable gaps remain. This article explores existing disparities within pediatric congenital heart disease care. Congenital heart disease, the most common birth defect and a leading cause of infant death, has garnered substantial attention, revealing certain disparities within the US health care system. Factors such as race, ethnicity, insurance coverage, socioeconomic status, and geographic location are all commonalities that significantly affect health disparities in pediatric congenital heart disease. This comprehensive review sheds light on disparities from diverse perspectives in pediatric care, demonstrates the inequities and inequalities leading to these disparities, presents effective solutions, and issues a call to action for providers, institutions, and the health care system. Recognizing and addressing these disparities is imperative for ensuring equitable care and enhancing the long-term well-being of children affected by congenital heart disease. Implementing robust, evidence-based frameworks that promote responsible and safe interventions is fundamental to enduring change.
PubMed: 38934870
DOI: 10.1161/JAHA.123.032415 -
Journal of the American Heart... Jun 2024High energy requirements and poor feeding can lead to growth failure in patients with ventricular septal defect (VSD), but effects of preoperative malnutrition on...
BACKGROUND
High energy requirements and poor feeding can lead to growth failure in patients with ventricular septal defect (VSD), but effects of preoperative malnutrition on surgical outcomes are poorly understood, especially in low-resource settings.
METHODS AND RESULTS
We analyzed a cohort of children <5 years of age undergoing VSD closure at 60 global centers participating in the International Quality Improvement Collaborative for Congenital Heart Disease, 2015 to 2020. We calculated adjusted odds ratios (ORs) for in-hospital death and major infection and adjusted coefficients for duration of intensive care unit stay for 4 measures of malnutrition: severe wasting (weight-for-height score, <-3), moderate wasting (-3
CONCLUSIONS
Malnutrition was associated with mortality, infection, and longer intensive care unit stay in a global cohort of children undergoing VSD closure.
PubMed: 38934862
DOI: 10.1161/JAHA.123.032662 -
Journal of the American Heart... Jun 2024The long-term impact of weight gain (WG) on cardiovascular outcomes among patients with atrial fibrillation (AF) is unclear.
BACKGROUND
The long-term impact of weight gain (WG) on cardiovascular outcomes among patients with atrial fibrillation (AF) is unclear.
METHODS AND RESULTS
We studied 62 871 (mean age, 72±12, 43% women) adult patients with AF evaluated at the University of Pittsburgh Medical Center between January 1, 2010, and May 13, 2021. Serial body mass index, risk factors, comorbidities, and subsequent death and hospitalization were ascertained and stratified according to percentage WG (≥0% to <5%, ≥5% to <10%, and ≥10%). Over 4.9±3.19 years of follow-up, 27 114 (43%) patients gained weight (61%, ≥0% to <5%; 23%, ≥5% to <10%; 16%, ≥10%). Patients with progressive WG were incrementally younger (<0.001) women (40%, 42%, and 47%) with lower median household income (=0.002) and active smoking (8%, 13% and 13%), and they were less likely to be on a non-vitamin K oral anticoagulant (39%, 37%, and 32%). WG was incrementally associated with a significant increase in risk of hospitalization for AF (≥10% WG; hazard ratio [HR], 1.2 [95% CI, 1.2-1.3]; <0.0001), heart failure (≥10% WG; HR, 1.44 [95% CI, 1.3-1.6]; <0.001; ≥5% to <10% WG; HR, 1.17 [95% CI, 1.1-1.2]; <0.001), myocardial infarction (≥10% WG; HR, 1.2 [95% CI, 1.3-1.6]; <0.001) and all-cause stroke (4.2%, 4.3%, and 5.6%) despite significantly lower mean CHADSVasc score (2.9±1.7, 2.7±1.6, and 2.7±1.7). Patients with more WG were significantly more likely to receive cardiac and electrophysiologic interventions.
CONCLUSIONS
Among patients with AF, WG is incrementally associated with increased hospitalization for cardiovascular causes, particularly heart failure, stroke, myocardial infarction, and AF.
PubMed: 38934853
DOI: 10.1161/JAHA.123.032550 -
Journal of the American Heart... Jun 2024We aimed to clarify the predictive value of cerebral small-vessel disease and intracranial large artery disease (LAD) observed in magnetic resonance imaging of the brain...
Small-Vessel Disease and Intracranial Large Artery Disease in Brain MRI Predict Dementia and Acute Coronary Syndrome, Respectively: A Prospective, Observational Study in the Population at High Vascular Risk.
BACKGROUND
We aimed to clarify the predictive value of cerebral small-vessel disease and intracranial large artery disease (LAD) observed in magnetic resonance imaging of the brain and magnetic resonance angiography on future vascular events and cognitive impairment.
METHODS AND RESULTS
Data were derived from a Japanese cohort with evidence of cerebral vessel disease on magnetic resonance imaging. This study included 862 participants who underwent magnetic resonance angiography after excluding patients with a modified Rankin Scale score >1 and Mini-Mental State Examination score <24. We evaluated small-vessel disease such as white matter hyperintensities and lacunes in magnetic resonance imaging and LAD with magnetic resonance angiography. Outcomes were incident stroke, dementia, acute coronary syndrome, and all-cause death. Over a median follow-up period of 4.5 years, 54 incident stroke, 39 cases of dementia, and 27 cases of acute coronary syndrome were documented. Both small-vessel disease (white matter hyperintensities and lacunes) and LAD were associated with stroke; however, only white matter hyperintensities were related to dementia. In contrast, only LAD was associated with acute coronary syndrome. Among the 357 patients with no prior history of stroke, coronary or peripheral artery disease, or atrial fibrillation, white matter hyperintensities emerged as the sole predictor of future stroke and dementia, while LAD was the sole predictor of acute coronary syndrome.
CONCLUSIONS
Among cerebral vessels, small-vessel disease could underlie the cognitive impairment while LAD was associated with coronary artery disease as atherosclerotic vessel disease.
PubMed: 38934848
DOI: 10.1161/JAHA.123.033512