Peri-partum cardiomyopathy (PPCM) is a frequently fatal disease that affects women near delivery, and occurs more frequently in women with pre-eclampsia and/or multiple gestation. The etiology of PPCM, or why it associates with pre-eclampsia, remains unknown. We show here that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble Flt1 (sFlt1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by sub-clinical cardiac dysfunction, the extent of which correlates with circulating levels of sFlt1. Exogenous sFlt1 alone caused diastolic dysfunction in wildtype mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFlt1. These data strongly suggest that PPCM is in large part a vascular disease, caused by excess anti-angiogenic signaling in the peri-partum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.

IMPORTANCE Firearm homicide is a leading cause of injury death in the United States, and there is considerable debate over the effectiveness of firearm policies. An analysis of the effectiveness of firearm laws on firearm homicide is important to understand optimal policies to decrease firearm homicide in the United States.OBJECTIVE To evaluate the association between firearm laws and preventing firearm homicides in the United States.EVIDENCE REVIEW We evaluated peer-reviewed articles from 1970 to 2016 focusing on the association between US firearm laws and firearm homicide. We searched PubMed, CINAHL, Lexis/Nexis, Sociological Abstracts, Academic Search Premier, the Index to Legal Periodicals and Books, and the references from the assembled articles. We divided laws into 5 categories: those that (1) curb gun trafficking, (2) strengthen background checks, (3) improve child safety, (4) ban military-style assault weapons, and (5) restrict firearms in public places and leniency in firearm carrying. The articles were assessed using the standardized Guide to Community Preventive Services data collection instrument and 5 additional quality metrics:(1) appropriate data source(s) and outcome measure(s) were used for the study, (2) the time frame studied was adequate, (3) appropriate statistical tests were used, (4) the analytic results were robust, and (5) the disaggregated results of control variables were consistent with the literature. FINDINGS In the aggregate, stronger gun policies were associated with decreased rates of firearm homicide, even after adjusting for demographic and sociologic factors. Laws that strengthen background checks and permit-to-purchase seemed to decrease firearm homicide rates. Specific laws directed at firearm trafficking, improving child safety, or the banning of military-style assault weapons were not associated with changes in firearm homicide rates. The evidence for laws restricting guns in public places and leniency in gun carrying was mixed. CONCLUSIONS AND RELEVANCEThe strength of firearm legislation in general, and laws related to strengthening background checks and permit-to-purchase in particular, is associated with decreased firearm homicide rates. High-quality research is important to further evaluate the effectiveness of these laws. Legislation is just 1 part of a multipronged approach that will be necessary to decrease firearm homicides in the United States.

Summary The transcriptional coactivators PGC-1α and PGC-1β are widely thought to be required for mitochondrial biogenesis and fiber typing in skeletal muscle. We show here that mice lacking both PGC-1s in myocytes do indeed have profoundly deficient mitochondrial respiration, but surprisingly have preserved mitochondrial content, isolated muscle contraction capacity, fiber type composition, in-cage ambulation, and voluntary running capacity. Most of these findings are recapitulated in cell culture, and thus cell-autonomous. Functional electron microscopy reveals normal cristae density with decreased cytochrome oxidase activity. These data lead to the following surprising conclusions: that PGC-1s are in fact dispensable for baseline muscle function, mitochondrial content, and fiber typing; that endurance fatigue at low workloads is not limited by muscle mitochondrial capacity; and that mitochondrial content and cristae density can be dissociated from respiratory capacity.

The benefits of integrating primary care and substance use disorder treatment are well known, yet true integration is difficult. We developed and evaluated a team-based model of integrated care within the primary care setting for HIV-infected substance users and substance users at risk for contracting HIV. Qualitative data were gathered via focus groups and satisfaction surveys to assess patients' views of the program, evaluate key elements for success, and provide recommendations for other programs. Key themes related to preferences for the convenience and efficiency of integrated care; support for a team-based model of care; a feeling that the program requirements offered needed structure; the importance of counseling and education; and how provision of concrete services improved overall well-being and quality of life. For patients who received buprenorphine/naloxone for opioid dependence, this was viewed as a major benefit. Our results support other studies that theorize integrated care could be of significant value for hard-to-reach populations and indicate that having a clinical team dedicated to providing substance use disorder treatment, HIV risk reduction, and case management services integrated into primary care clinics has the potential to greatly enhance the ability to serve a challenging population with unmet treatment needs.

Suicide is the second leading cause of death among youths aged 10 to 19 years in the United States, with rates nearly doubling during the past decade. Youths in impoverished communities are at increased risk for negative health outcomes; however, the association between pediatric suicide and poverty is not well understood.OBJECTIVE To assess the association between pediatric suicide rates and county-level poverty concentration.

BACKGROUND AND OBJECTIVE: Child maltreatment remains a problem in the United States, and individual poverty is a recognized risk factor for abuse. Children in impoverished communities are at risk for negative health outcomes, but the relationship of community poverty to child abuse fatalities is not known. Our objective was to evaluate the association between county poverty concentration and rates of fatal child abuse.

BackgroundDuchenne muscle dystrophy (DMD) afflicts 1 million boys in the US and has few effective treatments. Constitutive transgenic expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α improves skeletal muscle function in the murine “mdx” model of DMD, but how this occurs, or whether it can occur post-natally, is not known. The leading mechanistic hypotheses for the benefits conferred by PGC-1α include the induction of utrophin, a dystrophin homolog, and/or induction and stabilization of the neuromuscular junction.MethodsThe effects of transgenic overexpression of PGC-1β, a homolog of PGC-1α in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1α confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1α transgenic animals were crossed with the dystrophin utrophin double knock out (mdx/utrn-/-) mice, a more severe dystrophic model. Finally, we also examined the effect of post-natal induction of skeletal muscle-specific PGC-1α overexpression on muscle structure and function in mdx mice.ResultsWe show here that PGC-1β does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1β transgenesis protects as efficaciously as PGC-1α against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1α is overexpressed in mdx/utrn-/- mice, we find that PGC-1α dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1α overexpression to show that PGC-1α can protect against dystrophy even if activated post-natally, a more plausible therapeutic option.ConclusionsThese data demonstrate that PGC-1α can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1α is equally protective in the more severely affected mdx/utrn-/- mice, which more closely recapitulates the aggressive progression of muscle damage seen in DMD patients. The data also identify PGC-1β as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1α and PGC-1β protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.

IMPORTANCE Youth firearm-related deaths are a public health crisis in the US. The association between county-level poverty and the risk of firearm-related deaths among youth is unknown, however.OBJECTIVE To examine the association between county-level poverty concentration and firearm-related mortality rates in US youth. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study analyzed US firearm fatalities in children and young adults aged 5 to 24 years that occurred between January 1, 2007, and December 31, 2016. Data were obtained from the Centers for Disease Control and Prevention's Compressed Mortality File, and annual intercensal county population data were obtained from the US Census Bureau. Data analyses were conducted between November 1, 2019, and June 30, 2020.EXPOSURES County-level poverty was categorized into 5 groups: 0% to 4.9%, 5% to 9.9%, 10% to 14.9%, 15% to 19.9%, and Ն20% of the population living below the federal poverty level. MAIN OUTCOMES AND MEASURESThe main outcomes were firearm-related deaths in total and by specific intent (homicide, suicide, and unintentional) per 100 000 youths over the entire study period. Multivariable negative binomial regression models were used to analyze the association between firearm-related mortality rates and county poverty concentration, controlling for demographic variables, urbanicity, and statewide firearm prevalence. Adjusted incidence rate ratios (IRRs) were calculated, and statewide firearm prevalence was estimated. The population-attributable fraction (PAF) and years of potential life lost for each intent were calculated.RESULTS A total of 67 905 firearm-related deaths among youth (predominantly composed of 60 164 male individuals [88.6%]) from 2007 to 2016 were analyzed. Of these deaths, 42 512 were homicides (62.6%), 23 034 were suicides (33.9%), and 1627 were unintentional (2.4%). Firearm-related mortality risk increased in a stepwise manner with increasing county poverty concentration. Compared with counties with the lowest poverty concentration, counties with the highest poverty concentration had an increased rate of total firearm-related deaths (adjusted IRR, 2.29; 95% CI, 1.96-2.67), homicides (adjusted IRR, 3.55; 95% CI, 2.80-4.51), suicides (adjusted IRR, 1.45; 95% CI, 1.20-1.75), and unintentional deaths (adjusted IRR, 9.32; 95% CI, 2.32-37.4). The PAF was 0.51 (95% CI, 0.43-0.57) for all firearm-related deaths, 0.66 (95% CI, 0.57-0.73) for homicides, 0.30 (95% CI, 0.17-0.42) for suicides, and 0.86 (95% CI, 0.46-0.97) for unintentional deaths. This calculation translated to 34 292 firearm-related deaths that would not have occurred if all counties had the same risk as counties with the lowest poverty concentration. A total of 3 833 105 years of potential life lost was observed.CONCLUSIONS AND RELEVANCE This study found an association between firearm-related mortality rates among youth and county-level poverty concentration. With more than half of firearm-related deaths and two-thirds of firearm-related homicides potentially associated wi...