Advancing Human iPSC-Derived Cardiomyocyte Hypoxia Resistance for Cardiac Regenerative Therapies through a Systematic Assessment of In Vitro Conditioning.

Acute myocardial infarction (MI) is a sudden, severe cardiac ischemic event that results in the death of up to one billion cardiomyocytes (CMs) and subsequent decrease in cardiac function. Engineered cardiac tissues (ECTs) are a promising approach to deliver the necessary mass of CMs to remuscularize the heart. However, the hypoxic environment of the heart post-MI presents a critical challenge for CM engraftment. Here, we present a high-throughput, systematic study targeting several physiological features of human induced pluripotent stem cell-derived CMs (hiPSC-CMs), including metabolism, Wnt signaling, substrate, heat shock, apoptosis, and mitochondrial stabilization, to assess their efficacy in promoting ischemia resistance in hiPSC-CMs. The results of 2D experiments identify hypoxia preconditioning (HPC) and metabolic conditioning as having a significant influence on hiPSC-CM function in normoxia and hypoxia. Within 3D engineered cardiac tissues (ECTs), metabolic conditioning with maturation media (MM), featuring high fatty acid and calcium concentration, results in a 1.5-fold increase in active stress generation as compared to RPMI/B27 control ECTs in normoxic conditions. Yet, this functional improvement is lost after hypoxia treatment. Interestingly, HPC can partially rescue the function of MM-treated ECTs after hypoxia. Our systematic and iterative approach provides a strong foundation for assessing and leveraging in vitro culture conditions to enhance the hypoxia resistance, and thus the successful clinical translation, of hiPSC-CMs in cardiac regenerative therapies.

Local Supports to Break the Cycle: A Description of Intersectional Interventions to Address Adverse Childhood Experiences and Drug Overdose.

CONTEXT: Adverse childhood experiences (ACEs), substance use disorders (SUDs), and overdose are interconnected issues impacting individuals and communities at multiple levels of the social ecology and across generations. Few studies describe approaches that intentionally and simultaneously address these issues. PROGRAM: This paper examines activities of 15 sites across the country that were designed to simultaneously prevent ACEs, SUD, and overdose. This paper describes the work at the intersection as well as gaps and opportunities. Describing ways to implement intersectional programming may assist other organizations in taking similar steps in their communities. IMPLEMENTATION: From December 2020 through July 15, 2023, funded sites received technical assistance from the National Association of County and City Health Officials and the Centers for Disease Control and Prevention for 18 months to support the implementation, adaptation, and/or expansion of evidence-based programs to address ACEs, SUD, and overdose. EVALUATION: Activities were coded to identify intersectional interventions that addressed ACEs, SUD, and overdose. Most of the ACEs prevention strategies and overdose prevention priority areas/guiding principles from which communities could choose were represented. Most activities were implemented with caregivers and families and addressed ACEs through interventions to lessen harm or to promote social norms. Primary prevention and coordination of resources were the most used overdose prevention priority area/guiding principle. DISCUSSION: It is possible to address the intersection of ACEs, SUD, and overdose on a local level. Opportunities to further address the intersection include incorporating more secondary and tertiary prevention strategies, expanding economic supports, and increasing the work focused on equity.

Reoccurring Escherichia coli O157:H7 Strain Linked to Leafy Greens-Associated Outbreaks, 2016-2019.

Genomic characterization of an Escherichia coli O157:H7 strain linked to leafy greens-associated outbreaks dates its emergence to late 2015. One clade has notable accessory genomic content and a previously described mutation putatively associated with increased arsenic tolerance. This strain is a reoccurring, emerging, or persistent strain causing illness over an extended period.

The Martinsburg Initiative: A Collaboration Between Public Safety, Public Health, and Schools to Address Trauma and Substance Use.

The Martinsburg Initiative (TMI) is a community-based model developed in Martinsburg, West Virginia, that implements a comprehensive approach to adverse childhood experiences and substance use prevention and mitigation by leveraging partnerships in public health and health care, public safety, and education. TMI receives coordinated federal funding and technical assistance from the Centers for Disease Control and Prevention, the Washington-Baltimore High Intensity Drug Trafficking Agency, and the National Association of County and City Health Officials to integrate evidence-based and promising strategies. It advances such strategies by translating them for implementation within the community, evaluating the reach and potential impact of the model, and by engaging key stakeholders. Preliminary results describing program reach and short-term outcomes collected for a subset of the interventions during implementation are presented. The model uses touchpoints across multiple community sectors in the city of Martinsburg to break the cycle of trauma and substance use across the life span.

Azithromycin-resistant mph(A)-positive Salmonella enterica serovar Typhi in the United States.

OBJECTIVES: The United States Centers for Disease Control and Prevention (CDC) conducts active surveillance for typhoid fever cases caused by Salmonella enterica serovar Typhi (Typhi). Here we describe the characteristics of the first two cases of mph(A)-positive azithromycin-resistant Typhi identified through US surveillance. METHODS: Isolates were submitted to public health laboratories, sequenced, and screened for antimicrobial resistance determinants and plasmids, as part of CDC PulseNet's routine genomic surveillance. Antimicrobial susceptibility testing and long-read sequencing were also performed. Basic case information (age, sex, travel, outcome) was collected through routine questionnaires; additional epidemiological data was requested through follow-up patient interviews. RESULTS: The patients are related and both reported travel to India (overlapping travel dates) before illness onset. Both Typhi genomes belong to the GenoTyphi lineage 4.3.1.1 and carry the azithromycin-resistance gene mph(A) on a PTU-FE (IncFIA/FIB/FII) plasmid. These strains differ genetically from mph(A)-positive Typhi genomes recently reported from Pakistan, suggesting independent emergence of azithromycin resistance in India. CONCLUSIONS: Cases of typhoid fever caused by Typhi strains resistant to all available oral treatment options are cause for concern and support the need for vaccination of travellers to Typhi endemic regions. US genomic surveillance serves as an important global sentinel for detection of strains with known and emerging antimicrobial resistance profiles, including strains from areas where routine surveillance is not conducted.

Extensively Drug-Resistant Typhoid Fever in the United States.

Cases of extensively drug-resistant (XDR) typhoid fever have been reported in the United States among patients who did not travel internationally. Clinicians should consider if and where the patient traveled when selecting empiric treatment for typhoid fever. XDR typhoid fever should be treated with a carbapenem, azithromycin, or both.

Virtual optimization of guideline-directed medical therapy in hospitalized patients with heart failure with reduced ejection fraction: the IMPLEMENT-HF pilot study.

AIMS: Implementation of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains incomplete. Non-cardiovascular hospitalization may present opportunities for GDMT optimization. We assessed the efficacy and durability of a virtual, multidisciplinary 'GDMT Team' on medical therapy prescription for HFrEF. METHODS AND RESULTS: Consecutive hospitalizations in patients with HFrEF (ejection fraction ≤40%) were prospectively identified from 3 February to 1 March 2020 (usual care group) and 2 March to 28 August 2020 (intervention group). Patients with critical illness, de novo heart failure, and systolic blood pressure <90 mmHg in the preceeding 24 hs prior to enrollment were excluded. In the intervention group, a pharmacist-physician GDMT Team provided optimization suggestions to treating teams based on an evidence-based algorithm. The primary outcome was a GDMT optimization score, the sum of positive (+1 for new initiations or up-titrations) and negative therapeutic changes (-1 for discontinuations or down-titrations) at hospital discharge. Serious in-hospital safety events were assessed. Among 278 consecutive encounters with HFrEF, 118 met eligibility criteria; 29 (25%) received usual care and 89 (75%) received the GDMT Team intervention. Among usual care encounters, there were no changes in GDMT prescription during hospitalization. In the intervention group, ß-blocker (72% to 88%; P = 0.01), angiotensin receptor-neprilysin inhibitor (6% to 17%; P = 0.03), mineralocorticoid receptor antagonist (16% to 29%; P = 0.05), and triple therapy (9% to 26%; P < 0.01) prescriptions increased during hospitalization. After adjustment for clinically relevant covariates, the GDMT Team was associated with an increase in GDMT optimization score (+0.58; 95% confidence interval +0.09 to +1.07; P = 0.02). There were no serious in-hospital adverse events. CONCLUSIONS: Non-cardiovascular hospitalizations are a potentially safe and effective setting for GDMT optimization. A virtual GDMT Team was associated with improved heart failure therapeutic optimization. This implementation strategy warrants testing in a prospective randomized controlled trial.

The dirty work of promoting "recycling" of America's sewage sludge.

Serious illnesses, including deaths, and adverse environmental impacts have been linked to land application of sewage sludge. EPA and the wastewater treatment industry have worked with Congress to fund wastewater trade associations to promote land application, supporting industry-friendly scientists and discouraging independent research, to prevent local governments from restricting land application and to thwart litigation against municipalities and the industry.