Evaluation of a Virtual Training to Enhance Public Health Capacity for COVID-19 Infection Prevention and Control in Nursing Homes.

CONTEXT: Between April 2020 and May 2021, the Centers for Disease Control and Prevention (CDC) awarded more than $40 billion to health departments nationwide for COVID-19 prevention and response activities. One of the identified priorities for this investment was improving infection prevention and control (IPC) in nursing homes. PROGRAM: CDC developed a virtual course to train new and less experienced public health staff in core healthcare IPC principles and in the application of CDC COVID-19 healthcare IPC guidance for nursing homes. IMPLEMENTATION: From October 2020 to August 2021, the CDC led training sessions for 12 cohorts of public health staff using pretraining reading materials, case-based scenarios, didactic presentations, peer-learning opportunities, and subject matter expert-led discussions. Multiple electronic assessments were distributed to learners over time to measure changes in self-reported knowledge and confidence and to collect feedback on the course. Participating public health programs were also assessed to measure overall course impact. EVALUATION: Among 182 enrolled learners, 94% completed the training. Most learners were infection preventionists (42%) or epidemiologists (38%), had less than 1 year of experience in their health department role (75%), and had less than 1 year of subject matter experience (54%). After training, learners reported increased knowledge and confidence in applying the CDC COVID-19 healthcare IPC guidance for nursing homes (≥81%) with the greatest increase in performing COVID-19 IPC consultations and assessments (87%). The majority of participating programs agreed that the course provided an overall benefit (88%) and reduced training burden (72%). DISCUSSION: The CDC's virtual course was effective in increasing public health capacity for COVID-19 healthcare IPC in nursing homes and provides a possible model to increase IPC capacity for other infectious diseases and other healthcare settings. Future virtual healthcare IPC courses could be enhanced by tailoring materials to health department needs, reinforcing training through applied learning experiences, and supporting mechanisms to retain trained staff.

Analysis of Severe Adverse Events Reported Among Patients Receiving Isoniazid-Rifapentine Treatment for Latent Mycobacterium tuberculosis Infection-United States, 2012-2016.

We analyzed data from 2012 to 2016 for patients who were hospitalized or who died after ≥1 dose of isoniazid-rifapentine for treatment of latent Mycobacterium tuberculosis infection. No patients died; 15 were hospitalized. Nine patients experienced hypotension, and 5 had elevated serum aminotransferases, reinforcing the need for vigilant monitoring during treatment.

Severe Pulmonary Disease Associated with Electronic-Cigarette-Product Use - Interim Guidance.

On September 6, 2019, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). As of August 27, 2019, 215 possible cases of severe pulmonary disease associated with the use of electronic cigarette (e-cigarette) products (e.g., devices, liquids, refill pods, and cartridges) had been reported to CDC by 25 state health departments. E-cigarettes are devices that produce an aerosol by heating a liquid containing various chemicals, including nicotine, flavorings, and other additives (e.g., propellants, solvents, and oils). Users inhale the aerosol, including any additives, into their lungs. Aerosols produced by e-cigarettes can contain harmful or potentially harmful substances, including heavy metals such as lead, volatile organic compounds, ultrafine particles, cancer-causing chemicals, or other agents such as chemicals used for cleaning the device (1). E-cigarettes also can be used to deliver tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, or other drugs; for example, "dabbing" involves superheating substances that contain high concentrations of THC and other plant compounds (e.g., cannabidiol) with the intent of inhaling the aerosol. E-cigarette users could potentially add other substances to the devices. This report summarizes available information and provides interim case definitions and guidance for reporting possible cases of severe pulmonary disease. The guidance in this report reflects data available as of September 6, 2019; guidance will be updated as additional information becomes available.

Statistical Method to Detect Tuberculosis Outbreaks among Endemic Clusters in a Low-Incidence Setting.

We previously reported use of genotype surveillance data to predict outbreaks among incident tuberculosis clusters. We propose a method to detect possible outbreaks among endemic tuberculosis clusters. We detected 15 possible outbreaks, of which 10 had epidemiologic data or whole-genome sequencing results. Eight outbreaks were corroborated.

Increased Vaccine Uptake Among Eligible Patients at a Veterans Affairs Hospital Through an Inpatient COVID-19 Vaccination Program, Atlanta, Georgia, 2021.

OBJECTIVE: Inpatient vaccination is an opportunity to increase vaccine uptake among patients at high risk for severe COVID-19 illness. We designed and implemented a hospital-based COVID-19 vaccination program with the aim of increasing documentation of vaccine eligibility and COVID-19 vaccination to eligible inpatients before discharge. METHODS: We integrated a templated note into the electronic medical records and trained health care personnel to screen inpatients and document COVID-19 vaccine eligibility at the Atlanta Veterans Affairs Medical Center. Vaccination staff deployed to inpatient wards administered the vaccine to eligible and consenting patients at the bedside. We calculated the number of inpatients whose vaccine eligibility was assessed and documented during a 4-week period after health care personnel were trained. We used the Wald χ2 test to compare the proportion of eligible patients who were vaccinated before discharge 4 weeks before (March 29-April 23, 2021) and 4 weeks after (May 3-28, 2021) the training period. RESULTS: During the 4 weeks before the training period, COVID-19 vaccine eligibility was not routinely assessed and documented. Of 793 inpatients discharged during the 4 weeks after the training period, 470 (59%) had COVID-19 vaccine eligibility documented. Of 86 patients who were eligible for vaccination, 61 (71%) received COVID-19 vaccination before discharge. COVID-19 vaccination rates during hospitalization increased significantly from 16 of 769 inpatients (2%) during the 4 weeks before training to 61 of 793 inpatients (8%) during the 4 weeks after training (P < .001). CONCLUSION: An inpatient vaccination program that integrated COVID-19 vaccination into discharge planning increased vaccine screening and uptake. Future studies are needed to identify barriers to vaccination and strategies to increase vaccine uptake among those who are hesitant.

Molecular surveillance for large outbreaks of tuberculosis in the United States, 2014-2018.

OBJECTIVE: This study describes characteristics of large tuberculosis (TB) outbreaks in the United States detected using novel molecular surveillance methods during 2014-2016 and followed for 2 years through 2018. METHODS: We developed 4 genotype-based detection algorithms to identify large TB outbreaks of ≥10 cases related by recent transmission during a 3-year period. We used whole-genome sequencing and epidemiologic data to assess evidence of recent transmission among cases. RESULTS: There were 24 large outbreaks involving 518 cases; patients were primarily U.S.-born (85.1%) racial/ethnic minorities (84.1%). Compared with all other TB patients, patients associated with large outbreaks were more likely to report substance use, homelessness, and having been diagnosed while incarcerated. Most large outbreaks primarily occurred within residences among families and nonfamilial social contacts. A source case with a prolonged infectious period and difficulties in eliciting contacts were commonly reported contributors to transmission. CONCLUSION: Large outbreak surveillance can inform targeted interventions to decrease outbreak-associated TB morbidity.

Tuberculosis Genotype Clusters and Transmission in the U.S., 2009-2018.

INTRODUCTION: In the U.S., universal genotyping of culture-confirmed tuberculosis cases facilitates cluster detection. Early recognition of the small clusters more likely to become outbreaks can help prioritize public health resources for immediate interventions. METHODS: This study used national surveillance data reported during 2009-2018 to describe incident clusters (≥3 tuberculosis cases with matching genotypes not previously reported in the same county); data were analyzed during 2020. Cox proportional hazards regression models were used to examine the patient characteristics associated with clusters doubling in size to ≥6 cases. RESULTS: During 2009-2018, a total of 1,516 incident clusters (comprising 6,577 cases) occurred in 47 U.S. states; 231 clusters had ≥6 cases. Clusters of ≥6 cases disproportionately included patients who used substances, who had recently experienced homelessness, who were incarcerated, who were U.S. born, or who self-identified as being of American Indian or Alaska Native race or of Black race. A median of 54 months elapsed between the first and the third cases in clusters that remained at 3-5 cases compared with a median of 9.5 months in clusters that grew to ≥6 cases. The longer time between the first and third cases and the presence of ≥1 patient aged ≥65 years among the first 3 cases predicted a lower hazard for accumulating ≥6 cases. CONCLUSIONS: Clusters accumulating ≥3 cases within a year should be prioritized for intervention. Effective response strategies should include plans for targeted outreach to U.S.-born individuals, incarcerated people, those experiencing homelessness, people using substances, and individuals self-identifying as being of American Indian or Alaska Native race or of Black race.

Investigation of Bacterial Infections Among Patients Treated With Umbilical Cord Blood-Derived Products Marketed as Stem Cell Therapies.

Importance: The number of clinics marketing stem cell products for joint diseases, chronic pain, and most recently, COVID-19, has increased despite warnings from the US Food and Drug Administration that stem cell products for these and other indications have not been proven safe or effective. Objective: To examine bacterial infections in 20 patients who received umbilical cord blood-derived products marketed as stem cell treatment. Design, Setting, and Participants: This case series is a national public health investigation including case-finding, medical record review and abstraction, and laboratory investigation, including sterility testing of products and whole-genome sequencing of patient and product isolates. Participants included patients who developed bacterial infections following administration of umbilical cord blood-derived products marketed as stem cell treatment during August 2017 to September 2018. Data analysis was performed from March 2019 to September 2021. Exposures: Umbilical cord blood-derived products marketed as stem cell treatment. Main Outcomes and Measures: Data were collected on patient infections and exposures. The Centers for Disease Control and Prevention performed sterility testing on undistributed and distributed vials of product marketed as stem cell treatment and performed whole-genome sequencing to compare patient and product bacterial isolates. Results: Culture-confirmed bacterial infections were identified in 20 patients (median [range] age, 63 [2-89] years; 13 male patients [65%]) from 8 US states who sought stem cell treatment for conditions including pain, osteoarthritis, rheumatoid arthritis, and injury; all but 1 required hospitalization. The most frequently isolated bacteria from patients with infections were common enteric species, including Escherichia coli (14 patients) and Enterobacter cloacae (7 patients). Of unopened, undistributed products sampled for testing, 65% (22 of 34 vials) were contaminated with at least 1 of 16 bacterial species, mostly enteric. A patient isolate from Arizona matched isolates obtained from products administered to patients in Florida, and patient isolates from Texas matched undistributed product sent from the company in California. Conclusions and Relevance: Unapproved stem cell products can expose patients to serious risks without proven benefit. Sequencing results suggest a common source of extensive contamination, likely occurring during the processing of cord blood into product. Patients and health care practitioners who are considering the use of unapproved products marketed as stem cell treatment should be aware of their unproven benefits and potential risks, including serious infections.

MYCN-Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis.

MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1. Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence creates a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like N-acetyl-L-cysteine, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified neuroblastoma to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway. SIGNIFICANCE: This study shows how MYCN increases intracellular iron levels and subsequent GSH pathway activity and demonstrates the antitumor activity of FDA-approved SAS and auranofin in patient-derived xenograft models of MYCN-amplified neuroblastoma.

The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity.

PURPOSE: It was recently demonstrated that the EWSR1-FLI1 t(11;22)(q24;12) translocation contributes to the hypersensitivity of Ewing sarcoma to PARP inhibitors, prompting clinical evaluation of olaparib in a cohort of heavily pretreated Ewing sarcoma tumors. Unfortunately, olaparib activity was disappointing, suggesting an underappreciated resistance mechanism to PARP inhibition in patients with Ewing sarcoma. We sought to elucidate the resistance factors to PARP inhibitor therapy in Ewing sarcoma and identify a rational drug combination capable of rescuing PARP inhibitor activity. EXPERIMENTAL DESIGN: We employed a pair of cell lines derived from the same patient with Ewing sarcoma prior to and following chemotherapy, a panel of Ewing sarcoma cell lines, and several patient-derived xenograft (PDX) and cell line xenograft models. RESULTS: We found olaparib sensitivity was diminished following chemotherapy. The matched cell line pair revealed increased expression of the antiapoptotic protein BCL-2 in the chemotherapy-resistant cells, conferring apoptotic resistance to olaparib. Resistance to olaparib was maintained in this chemotherapy-resistant model in vivo, whereas the addition of the BCL-2/XL inhibitor navitoclax led to tumor growth inhibition. In 2 PDXs, olaparib and navitoclax were minimally effective as monotherapy, yet induced dramatic tumor growth inhibition when dosed in combination. We found that EWS-FLI1 increases BCL-2 expression; however, inhibition of BCL-2 alone by venetoclax is insufficient to sensitize Ewing sarcoma cells to olaparib, revealing a dual necessity for BCL-2 and BCL-XL in Ewing sarcoma survival. CONCLUSIONS: These data reveal BCL-2 and BCL-XL act together to drive olaparib resistance in Ewing sarcoma and reveal a novel, rational combination therapy that may be put forward for clinical trial testing.

Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression.

Purpose: Small-cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% 5-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets.Experimental Design: We used a high-throughput drug screen to identify a venetoclax-sensitive SCLC subpopulation and validated the findings with multiple patient-derived xenografts of SCLC.Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of patients with SCLC could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs.Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2-expressing SCLCs. Clin Cancer Res; 24(2); 360-9. ©2017 AACR.

Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma.

High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death. Retinoic acid (RA)-resistant neuroblastoma cells were sensitive to GSK-J4. In addition, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Furthermore, GSK-J4 and RA combination increased differentiation and ER stress over GSK-J4 effects and limited the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, PUMA induction by GSK-J4 sensitized tumors to the B cell lymphoma 2 (BCL-2) inhibitor venetoclax, demonstrating that epigenetic-targeted therapies and BCL-2 homology domain 3 mimetics can be rationally combined to treat this high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust antineuroblastoma activity.

Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target.

Purpose: EGFR inhibitors (EGFRi) are effective against EGFR-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M We recently demonstrated that T790M can arise de novo during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like T790M Experimental Design: We have developed DTCs to EGFRi in EGFR-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR-mutant lung cancer tumors in vivo Results: We demonstrate surviving EGFR-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivo Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. Clin Cancer Res; 24(22); 5658-72. ©2018 AACR.

Tuberculosis Outbreaks in the United States, 2009-2015.

OBJECTIVES: The Centers for Disease Control and Prevention provides on-site epidemiologic assistance for outbreak response when the health capacity of state, tribal, local, and territorial health departments has been exceeded. We examined recent outbreaks of tuberculosis (TB) for which health departments needed assistance. METHODS: We defined a TB outbreak as detection of ≥3 TB cases related by transmission, as suggested by routine genotyping and epidemiologic linkages. We conducted retrospective reviews of documentation from all 21 TB outbreak investigations in the United States for which the Centers for Disease Control and Prevention provided on-site assistance during 2009-2015. We abstracted data on patients' demographic characteristics and TB risk factors, as well as factors contributing to the outbreak from trip reports written by on-site investigators, and we compared these with outbreaks investigated during 2002-2008. RESULTS: The 21 TB outbreaks during 2009-2015 involved 457 outbreak patients (range, 3-99 patients per outbreak). Of the 21 outbreaks, 16 were first identified through genotype data. In sum, 118 (26%) patients were identified through contact investigations of other patients in the outbreak. Most outbreak patients (n = 363, 79%) were US born. Ninety-two (26%) patients had a mental illness, 204 (45%) had been homeless in the year before diagnosis, and 379 (83%) used alcohol excessively or used illicit substances. The proportion of patients experiencing homelessness doubled between 2002-2008 and 2009-2015; other characteristics were similar between the 2 periods. Delayed TB diagnosis contributed to unmitigated transmission in all but 1 outbreak. CONCLUSIONS: TB outbreaks challenge frontline public health resources. Genotyping and contact investigations are important strategies for detecting and controlling TB outbreaks, particularly among people experiencing homelessness or those with mental illness.

Tuberculosis Among Incarcerated Hispanic Persons in the United States, 1993-2014.

We examined the National tuberculosis surveillance system to describe Hispanic persons who were incarcerated at time of tuberculosis (TB) diagnosis and to compare their characteristics with those of non-Hispanic incarcerated TB patients. After declines between 1993 and 2002, the annual proportion of Hispanic TB patients who were incarcerated grew from 4.9% in 2003 to 8.4% in 2014. During 2003-2014, 19% of incarcerated US-born TB patients were Hispanic, and 86% of the foreign-born were Hispanic. Most incarcerated TB patients were in local jails, but about a third of all foreign-born Hispanics were in the facility category that includes Immigration and Customs Enforcement detention centers. Foreign birth and recent U.S. arrival characterized many Hispanic persons receiving a TB diagnosis while incarcerated. Hispanic patients had twice the odds of being in federal prisons. Systematic efforts to identify TB infection and disease might lead to early diagnoses and prevention of future cases.

Outbreak of Drug-Resistant Mycobacterium tuberculosis Among Homeless People in Atlanta, Georgia, 2008-2015.

OBJECTIVES: Our objective was to describe and determine the factors contributing to a recent drug-resistant tuberculosis (TB) outbreak in Georgia. METHODS: We defined an outbreak case as TB diagnosed from March 2008 through December 2015 in a person residing in Georgia at the time of diagnosis and for whom (1) the genotype of the Mycobacterium tuberculosis isolate was consistent with the outbreak strain or (2) TB was diagnosed clinically without a genotyped isolate available and connections were established to another outbreak-associated patient. To determine factors contributing to transmission, we interviewed patients and reviewed health records, homeless facility overnight rosters, and local jail booking records. We also assessed infection control measures in the 6 homeless facilities involved in the outbreak. RESULTS: Of 110 outbreak cases in Georgia, 86 (78%) were culture confirmed and isoniazid resistant, 41 (37%) occurred in people with human immunodeficiency virus coinfection (8 of whom were receiving antiretroviral treatment at the time of TB diagnosis), and 10 (9%) resulted in TB-related deaths. All but 8 outbreak-associated patients had stayed overnight or volunteered extensively in a homeless facility; all these facilities lacked infection control measures. At least 9 and up to 36 TB cases outside Georgia could be linked to this outbreak. CONCLUSIONS: This article highlights the ongoing potential for long-lasting and far-reaching TB outbreaks, particularly among populations with untreated human immunodeficiency virus infection, mental illness, substance abuse, and homelessness. To prevent and control TB outbreaks, health departments should work with overnight homeless facilities to implement infection control measures and maintain searchable overnight rosters.