(Am J Public Health. Published online ahead of print June 10, 2021 e1-e7. https//doi.org/10.2105/AJPH.2021.3062727).Background Ischemia/reperfusion injury impairs proteostasis, and triggers adaptive cellular responses, such as the unfolded protein response (UPR), which functions to restore endoplasmic reticulum homeostasis. After cardiac arrest (CA) and resuscitation, the UPR is activated in various organs including the brain. However, the role of the UPR in CA has remained largely unknown. Here we aimed to investigate effects of activation of the ATF6 (activating transcription factor 6) UPR branch in CA. Methods and Results Conditional and inducible sATF6-KI (short-form ATF6 knock-in) mice and a selective ATF6 pathway activator 147 were used. CA was induced in mice by KCl injection, followed by cardiopulmonary resuscitation. We first found that neurologic function was significantly improved, and neuronal damage was mitigated after the ATF6 pathway was activated in neurons of sATF6-KI mice subjected to CA/cardiopulmonary resuscitation. Further RNA sequencing analysis indicated that such beneficial effects were likely attributable to increased expression of pro-proteostatic genes regulated by ATF6. Especially, key components of the endoplasmic reticulum-associated degradation process, which clears potentially toxic unfolded/misfolded proteins in the endoplasmic reticulum, were upregulated in the sATF6-KI brain. Accordingly, the CA-induced increase in K48-linked polyubiquitin in the brain was higher in sATF6-KI mice relative to control mice. Finally, CA outcome, including the survival rate, was significantly improved in mice treated with compound 147. Conclusions This is the first experimental study to determine the role of the ATF6 UPR branch in CA outcome. Our data indicate that the ATF6 UPR branch is a prosurvival pathway and may be considered as a therapeutic target for CA.Background Pulmonary hypertension (PH) is a common complication in patients with Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a severe congenital disorder associated with mutations in the FOXF1 gene. While the loss of alveolar microvasculature causes PH in ACDMPV patients, it is unknown whether increasing neonatal lung angiogenesis could prevent PH and right ventricular (RV) hypertrophy. Methods We used echocardiography, RV catheterization, immunostaining and biochemical methods to examine lung and heart remodeling and RV output in Foxf1WT/S52F mice carrying the S52F Foxf1 mutation (identified in ACDMPV patients). The ability of Foxf1WT/S52F mutant embryonic stem cells (ESCs) to differentiate into respiratory cell lineages in vivo was examined using blastocyst complementation. Intravascular delivery of nanoparticles with a non-integrating Stat3 expression vector was used to improve neonatal pulmonary angiogenesis in Foxf1WT/S52F mice and determine its effects on PH and RV hypertrophy. Results Foxf1WT/S52F mice developed PH and RV hypertrophy after birth. The severity of PH in Foxf1WT/S52F mice directly correlated with mortality, low body weight, pulmonary artery muscularization and increased collagen deposition in the lung tissue. Increased fibrotic remodeling was found in human ACDMPV lungs. Mouse ESCs carrying the S52F Foxf1 mutation were used to produce chimeras via blastocyst complementation and to demonstrate that Foxf1WT/S52F ESCs have a propensity to differentiate into pulmonary myofibroblasts. Intravascular delivery of nanoparticles carrying Stat3 cDNA protected Foxf1WT/S52F mice from RV hypertrophy and PH, improved survival and decreased fibrotic lung remodeling. Conclusions Nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent PH in ACDMPV.This article explores a tension at the core of the concept of herd immunity that has been overlooked in public and scientific discussions‒namely how can immunity, a phenomenon of individual biological defenses, be made relevant to populations? How can collectives be considered "immune"? Over the course of more than a century of use of the term, scientists have developed many different understandings of the concept in response to this inherent tension. Originating among veterinary scientists in the United States in the late 19th century, the concept was adopted by British scientists researching human infectious disease by the early 1920s. It soon became a staple concept for epidemiologists interested in disease ecology, helping to articulate the population dynamics of diseases such as diphtheria and influenza. Finally, though more traditional understandings of the concept remained in scientific use, in the era after World War II, it increasingly came to signal the objective and outcome of mass vaccination. Recognizing the complexity of scientific efforts to resolve the paradox of herd immunity may help us consider the best distribution of immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).(Am J Public Health. Published online ahead of print June 10, 2021 e1-e8. https://www.selleckchem.com/products/LBH-589.html https//doi.org/10.2105/AJPH.2021.306264).Objectives. To estimate excess all-cause mortality in Philadelphia, Pennsylvania, during the COVID-19 pandemic and understand the distribution of excess mortality in the population. Methods. With a Poisson model trained on recent historical data from the Pennsylvania vital registration system, we estimated expected weekly mortality in 2020. We compared these estimates with observed mortality to estimate excess mortality. We further examined the distribution of excess mortality by age, sex, and race/ethnicity. Results. There were an estimated 3550 excess deaths between March 22, 2020, and January 2, 2021, a 32% increase above expectations. Only 77% of excess deaths (n = 2725) were attributed to COVID-19 on the death certificate. Excess mortality was disproportionately high among older adults and people of color. Sex differences varied by race/ethnicity. Conclusions. Excess deaths during the pandemic were not fully explained by COVID-19 mortality; official counts significantly undercount the true death toll. Far from being a great equalizer, the COVID-19 pandemic has exacerbated preexisting disparities in mortality by race/ethnicity. Public Health Implications. Mortality data must be disaggregated by age, sex, and race/ethnicity to accurately understand disparities among groups.