Developing National Genotype-Independent Indicators for Recent Mycobacterium Tuberculosis Transmission Using Pediatric Cases-United States, 2011-2017.

INTRODUCTION: Pediatric tuberculosis (TB) cases are sentinel events for Mycobacterium tuberculosis transmission in communities because children, by definition, must have been infected relatively recently. However, these events are not consistently identified by genotype-dependent surveillance alerting methods because many pediatric TB cases are not culture-positive, a prerequisite for genotyping. METHODS: We developed 3 potential indicators of ongoing TB transmission based on identifying counties in the United States with relatively high pediatric (aged <15 years) TB incidence: (1) a case proportion indicator: an above-average proportion of pediatric TB cases among all TB cases; (2) a case rate indicator: an above-average pediatric TB case rate; and (3) a statistical model indicator: a statistical model based on a significant increase in pediatric TB cases from the previous 8-quarter moving average. RESULTS: Of the 249 US counties reporting ≥2 pediatric TB cases during 2009-2017, 240 and 249 counties were identified by the case proportion and case rate indicators, respectively. The statistical model indicator identified 40 counties with a significant increase in the number of pediatric TB cases. We compared results from the 3 indicators with an independently generated list of 91 likely transmission events involving ≥2 pediatric cases (ie, known TB outbreaks or case clusters with reported epidemiologic links). All counties with likely transmission events involving multiple pediatric cases were identified by ≥1 indicator; 23 were identified by all 3 indicators. PRACTICE IMPLICATIONS: This retrospective analysis demonstrates the feasibility of using routine TB surveillance data to identify counties where ongoing TB transmission might be occurring, even in the absence of available genotyping data.

Screening for SARS-CoV-2 Infection Within a Psychiatric Hospital and Considerations for Limiting Transmission Within Residential Psychiatric Facilities - Wyoming, 2020.

In the United States, approximately 180,000 patients receive mental health services each day at approximately 4,000 inpatient and residential psychiatric facilities (1). SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), can spread rapidly within congregate residential settings (2-4), including psychiatric facilities. On April 13, 2020, two patients were transferred to Wyoming's state psychiatric hospital from a private psychiatric hospital that had confirmed COVID-19 cases among its residents and staff members (5). Although both patients were asymptomatic at the time of transfer and one had a negative test result for SARS-CoV-2 at the originating facility, they were both isolated and received testing upon arrival at the state facility. On April 16, 2020, the test results indicated that both patients had SARS-CoV-2 infection. In response, the state hospital implemented expanded COVID-19 infection prevention and control (IPC) procedures (e.g., enhanced screening, testing, and management of new patient admissions) and adapted some standard IPC measures to facilitate implementation within the psychiatric patient population (e.g., use of modified face coverings). To assess the likely effectiveness of these procedures and determine SARS-CoV-2 infection prevalence among patients and health care personnel (HCP) (6) at the state hospital, a point prevalence survey was conducted. On May 1, 2020, 18 days after the patients' arrival, 46 (61%) of 76 patients and 171 (61%) of 282 HCP had nasopharyngeal swabs collected and tested for SARS-CoV-2 RNA by reverse transcription-polymerase chain reaction. All patients and HCP who received testing had negative test results, suggesting that the hospital's expanded IPC strategies might have been effective in preventing the introduction and spread of SARS-CoV-2 infection within the facility. In congregate residential settings, prompt identification of COVID-19 cases and application of strong IPC procedures are critical to ensuring the protection of other patients and staff members. Although standard guidance exists for other congregate facilities (7) and for HCP in general (8), modifications and nonstandard solutions might be needed to account for the specific needs of psychiatric facilities, their patients, and staff members.

Evaluating the public health response to a mass bat exposure-Wyoming, 2017.

Mass bat exposures (MBEs) occur when multiple people are exposed to a bat or a bat colony, often over an extended period. In August 2017, a public health investigation was started in response to an MBE that occurred during May-August 2017 at a national park research station in Wyoming. We identified 176 people who had slept primarily in two lodges (Lodges A and B) at the research station, and successfully contacted 165 (93.8%) of these individuals. Risk assessments (RAs) were administered to all 165 individuals to determine degree and type of exposures to bats (e.g., biting or scratching). Exposure status for research station guests was classified as "non-exposed," "low risk" or "high risk," and counselling was provided to guide post-exposure prophylaxis (PEP) recommendations. Prior to public health notification and intervention, 19 persons made the decision to pursue PEP. The healthcare-seeking behaviours of this group were taken to represent outcomes in the absence of public health intervention. (These persons received a RA, and their risk classification was retrospectively assigned.) Approximately 1-2 weeks after conducting the RAs, we conducted a follow-up survey to determine whether recommendations regarding PEP were ultimately followed. The proportion of individuals that unnecessarily pursued PEP was higher among the 19 individuals that sought health care prior to receiving the RA (p < 0.00001). Among those receiving the RA first, all persons classified as high risk followed public health guidance to seek PEP treatment. Despite this, upon re-interview, only 21/79 (26.6%) of guests could accurately recall their risk classification, with most people (55.7%) overestimating their risk. Study findings demonstrate that early public health interventions such as RAs can reduce unnecessary use of PEP and that messaging used during rabies counselling should be clear.

Francisella tularensis Exposure Among National Park Service Employees During an Epizootic: Devils Tower National Monument, Wyoming, 2015.

Introduction: Tularemia is a zoonotic infection caused by the highly infectious bacterium Francisella tularensis. Persons having outdoor professions are more likely than others to be exposed to F. tularensis through increased contact with arthropods, infected animals, and contaminated aerosols. Materials and Methods: After a tularemia epizootic during July and August 2015 at Devils Tower National Monument and an associated tularemia infection in a park employee, we assessed seroprevalence of F. tularensis antibodies, risk factors for F. tularensis seropositivity, and use of protective measures among park employees. Results: Seroprevalence among participating employees was 13% (3/23). Seropositive employees reported multiple risk factors for F. tularensis exposure through both job-related and recreational activities. Activities reported by more seropositive than seronegative employees included using a power blower (67% vs. 5%, p = 0.03), collecting animal carcasses (100% vs. 30%, p = 0.047), and hunting prairie dogs recreationally (67% vs. 5%, p = 0.03). Seropositive employees reported exposure to more ticks (median 30, range 25-35) than seronegative employees (median 6, range 0-25, p = 0.001). Most employees used protective measures (e.g., insect repellent) inconsistently but increased use after receiving educational materials. Conclusions: Educating and enabling at-risk employees to use protective measures consistently, both at work and during recreational activities, can reduce exposure during epizootics.

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.

Evaluation of the Completeness, Data Quality, and Timeliness of Fetal Mortality Surveillance in Wyoming, 2006-2013.

Purpose The number of fetal deaths in the United States each year exceeds that of infant deaths. High quality fetal death certificate data are necessary for states to effectively address preventable fetal deaths. We evaluated completeness of detection of fetal deaths among Wyoming residents that occur out-of-state, quality of cause-of-death data, and timeliness of Wyoming fetal death certificate registration during 2006-2013. Description The numbers of out-of-state fetal deaths among Wyoming residents recorded by Wyoming surveillance and reported by the National Vital Statistics System were compared. Quality of cause-of-death data was assessed by calculating percentage of fetal death certificates completed in Wyoming with ill-defined, unknown, or missing cause-of-death entries. Timeliness was determined using the time between the fetal death and filing of the fetal death certificate with the Wyoming Department of Health Vital Statistics Service. Assessment Wyoming surveillance detected none of the 76 out-of-state fetal deaths among Wyoming residents reported by the National Vital Statistics System. Among 263 fetal death certificates completed in Wyoming and collected by Wyoming surveillance, 108 (41%) contained ill-defined, unknown, or missing cause-of-death entries. Median duration between the fetal death and filing with the Wyoming Vital Statistics Service was 33 days. Conclusion Wyoming fetal mortality surveillance is limited by failure to register out-of-state fetal deaths among residents, poor quality of cause-of-death data, and lack of timeliness. Strategies to improve surveillance include automating interjurisdictional sharing of fetal death data, certifier education, and electronic fetal death registration.

Gastrointestinal Illness Associated with Rancid Tortilla Chips at a Correctional Facility - Wyoming, 2015.

On October 12, 2015, a county health department notified the Wyoming Department of Health of an outbreak of gastrointestinal illness among residents and staff members at a local correctional facility. The majority of ill persons reported onset of symptoms within 1-3 hours after eating lunch served at the facility cafeteria at noon on October 11. Residents and staff members reported that tortilla chips served at the lunch tasted and smelled like chemicals. The Wyoming Department of Health and county health department personnel conducted case-control studies to identify the outbreak source. Consuming lunch at the facility on October 11 was highly associated with illness; multivariate logistic regression analysis found that tortilla chips were the only food item associated with illness. Hexanal and peroxide, markers for rancidity, were detected in tortilla chips and composite food samples from the lunch. No infectious agent was detected in human stool specimens or food samples. Extensive testing of lunch items did not identify any unusual chemical. Epidemiologic and laboratory evidence implicated rancid tortilla chips as the most likely source of illness. This outbreak serves as a reminder to consider alternative food testing methods during outbreaks of unusual gastrointestinal illness when typical foodborne pathogens are not identified. For interpretation of alternative food testing results, samples of each type of food not suspected to be contaminated are needed to serve as controls.

Human Rabies - Wyoming and Utah, 2015.

In September 2015, a Wyoming woman was admitted to a local hospital with a 5-day history of progressive weakness, ataxia, dysarthria, and dysphagia. Because of respiratory failure, she was transferred to a referral hospital in Utah, where she developed progressive encephalitis. On day 8 of hospitalization, the patient's family told clinicians they recalled that, 1 month before admission, the woman had found a bat on her neck upon waking, but had not sought medical care. The patient's husband subsequently had contacted county invasive species authorities about the incident, but he was not advised to seek health care for evaluation of his wife's risk for rabies. On October 2, CDC confirmed the patient was infected with a rabies virus variant that was enzootic to the silver-haired bat (Lasionycteris noctivagans). The patient died on October 3. Public understanding of rabies risk from bat contact needs to be improved; cooperation among public health and other agencies can aid in referring persons with possible bat exposure for assessment of rabies risk.

Travel-Associated Zika Virus Disease Cases Among U.S. Residents--United States, January 2015-February 2016.

Zika virus is an emerging mosquito-borne flavivirus. Recent outbreaks of Zika virus disease in the Pacific Islands and the Region of the Americas have identified new modes of transmission and clinical manifestations, including adverse pregnancy outcomes. However, data on the epidemiology and clinical findings of laboratory-confirmed Zika virus disease remain limited. During January 1, 2015-February 26, 2016, a total of 116 residents of 33 U.S. states and the District of Columbia had laboratory evidence of recent Zika virus infection based on testing performed at CDC. Cases include one congenital infection and 115 persons who reported recent travel to areas with active Zika virus transmission (n = 110) or sexual contact with such a traveler (n = 5). All 115 patients had clinical illness, with the most common signs and symptoms being rash (98%; n = 113), fever (82%; 94), and arthralgia (66%; 76). Health care providers should educate patients, particularly pregnant women, about the risks for, and measures to prevent, infection with Zika virus and other mosquito-borne viruses. Zika virus disease should be considered in patients with acute onset of fever, rash, arthralgia, or conjunctivitis, who traveled to areas with ongoing Zika virus transmission (http://www.cdc.gov/zika/geo/index.html) or who had unprotected sex with a person who traveled to one of those areas and developed compatible symptoms within 2 weeks of returning.

Notes from the Field: Group A Streptococcal Pharyngitis Misdiagnoses at a Rural Urgent-Care Clinic--Wyoming, March 2015.

Group A Streptococcus (GAS) is the most common bacterial cause of pharyngitis, implicated in 20%-30% of pediatric and 5%-15% of adult health care visits for sore throat (1). Along with the sudden onset of throat pain, GAS pharyngitis symptoms include fever, headache, and bilateral tender cervical lymphadenopathy (1,2). Accurate diagnosis and management of GAS pharyngitis is critical for limiting antibiotic overuse and preventing rheumatic fever (2), but distinguishing between GAS and viral pharyngitis clinically is challenging (1). Guidelines for diagnosis and management of GAS pharyngitis have been published by the Infectious Diseases Society of America (IDSA)* (1). IDSA recommends that patients with sore throat be tested for GAS to distinguish between GAS and viral pharyngitis; however, IDSA emphasizes the use of selective testing based on clinical symptoms and signs to avoid identifying GAS carriers rather than acute GAS infections (1). Therefore, testing for GAS usually is not recommended for the following: patients with sore throat and accompanying symptoms (e.g., cough, rhinorrhea) that strongly suggest a viral etiology; children aged <3 years, because acute rheumatic fever is extremely rare in this age group; and asymptomatic household contacts of patients with GAS pharyngitis (1). IDSA recommends penicillin or amoxicillin as the treatment of choice based on effectiveness and narrow spectrum of activity. To date, penicillin-resistant GAS has never been documented (1).

Anx2 interacts with HIV-1 Gag at phosphatidylinositol (4,5) bisphosphate-containing lipid rafts and increases viral production in 293T cells.

The neuronal damage characteristic of HIV-1-mediated CNS diseases is inflicted by HIV-1 infected brain macrophages. Several steps of viral replication, including assembly and budding, differ between macrophages and T cells; it is likely that cell-specific host factors mediate these differences. We previously defined Annexin 2 (Anx2) as an HIV Gag binding partner in human monocyte-derived macrophages (MDMs) that promotes proper viral assembly. Anx2, a calcium-dependent membrane-binding protein that can aggregate phospholipid-containing lipid rafts, is expressed to high levels in macrophages, but not in T lymphocytes or the 293T cell line. Here, we use bimolecular fluorescence complementation in the 293T cell model to demonstrate that Anx2 and HIV-1 Gag interact at the phosphatidylinositol (4,5) bisphosphate-containing lipid raft membrane domains at which Gag mediates viral assembly. Furthermore, we demonstrate that Anx2 expression in 293T cells increases Gag processing and HIV-1 production. These data provide new evidence that Anx2, by interacting with Gag at the membranes that support viral assembly, functions in the late stages of HIV-1 replication.

Annexin 2: a novel human immunodeficiency virus type 1 Gag binding protein involved in replication in monocyte-derived macrophages.

Human immunodeficiency virus (HIV) replication in the major natural target cells, CD4+ T lymphocytes and macrophages, is parallel in many aspects of the virus life cycle. However, it differs as to viral assembly and budding, which take place on plasma membranes in T cells and on endosomal membranes in macrophages. It has been postulated that cell type-specific host factors may aid in directing viral assembly to distinct destinations. In this study we defined annexin 2 (Anx2) as a novel HIV Gag binding partner in macrophages. Anx2-Gag binding was confined to productively infected macrophages and was not detected in quiescently infected monocyte-derived macrophages (MDM) in which an HIV replication block was mapped to the late stages of the viral life cycle (A. V. Albright, R. M. Vos, and F. Gonzalez-Scarano, Virology 325:328-339, 2004). We demonstrate that the Anx2-Gag interaction likely occurs at the limiting membranes of late endosomes/multivesicular bodies and that Anx2 depletion is associated with a significant decline in the infectivity of released virions; this coincided with incomplete Gag processing and inefficient incorporation of CD63. Cumulatively, our data suggest that Anx2 is essential for the proper assembly of HIV in MDM.

High-affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation.

BACKGROUND: A wide variety of antidepressants act as noncompetitive antagonists of nicotinic acetylcholine receptors (nAChRs), but the relationship between this antagonism and the therapeutic effects of antidepressants is unknown. METHODS: Antidepressant properties of the noncompetitive nAChR antagonist mecamylamine in the forced swim test were tested alone and in combination with the tricyclic antidepressant amitriptyline. Mice lacking high-affinity nAChRs were tested in three behavioral models to determine whether these receptors are required for behavioral effects of amitriptyline in common models of antidepressant action. Finally, the brains of wild-type and knockout animals treated with amitriptyline were examined to determine whether high-affinity nAChRs are required for antidepressant-induced increases in hippocampal cell proliferation. RESULTS: Inhibition of nAChRs by mecamylamine had antidepressant-like effects in the forced swim test and potentiated the antidepressant activity of amitriptyline when the two drugs were used in combination. Mice lacking high-affinity nAChRs showed no behavioral response to amitriptyline. Finally, after chronic treatment with amitriptyline, nAChR knockout mice did not show the increase in hippocampal cell proliferation seen in wild-type mice. CONCLUSIONS: These data support the hypothesis that antagonism of nAChRs is an essential component of the therapeutic action of antidepressants.

Alteration of hippocampal cell proliferation in mice lacking the beta 2 subunit of the neuronal nicotinic acetylcholine receptor.

Adult hippocampal neurogenesis declines with age in parallel with decreased performance on a variety of hippocampal-dependent tasks. We measured the rate of cellular proliferation in the hippocampus of mice lacking the beta 2-subunit of the nicotinic acetylcholine receptor (beta 2-/- mice) at three ages: young adult (3 months old), fully adult (7-10 months old), and aged (22-24 months old). Consistent with previous studies, we observed an age-related decline in hippocampal proliferation in both groups. However, in fully adult beta 2-/- mice a 43% reduction of granule cell proliferation was detected compared to age-matched controls. This was accompanied by a significant decrease in dentate gyrus area/section and the length of the granule cell layer in beta 2-/- mice. These alterations were not the result of a change in plasma corticosterone levels or expression of the neurotrophic factor BDNF in the dentate gyrus, two known regulators of hippocampal cell proliferation. Similarly, there was no increase in gliosis, abnormal myelination, or apoptotic cell death in the beta 2-/- animals, although there was a significant shift in the location of apoptotic cells in the dentate gyrus indicative of a change in neuronal survival. These results suggest that the beta 2-subunit containing nicotinic acetylcholine receptors play an important role in regulating cell proliferation in the hippocampus and that endogenous acetylcholine may act to oppose the negative effects of normal aging and stress on cellular proliferation.

Nestin promoter/enhancer directs transgene expression to precursors of adult generated periglomerular neurons.

The subventricular zone (SVZ) is a major neurogenic region in the adult brain. Cells from the SVZ give rise to two populations of olfactory bulb interneurons: the granule cells and periglomerular (PG) cells. Currently, little is known about the signaling pathways that direct these newly generated neurons to become either granule or PG neurons. In the present study, we used the nestin promoter and enhancer to direct expression of the tetracycline transactivator (tTA). We generated two independent strains of nestin-tTA transgenic animals and crossed founder mice from both lines to mice containing a tetracycline-regulated transgene (mCREB) whose expression served as a marker for the activity of the nestin-tTA transgene. mCREB expression occurred in a subset of proliferating cells in the SVZ and rostral migratory stream in both lines. Surprisingly, in both lines of nestin-tTA mice transgene expression in the olfactory bulb was limited to PG neurons and was absent from granule cells, suggesting that this nestin promoter construct differentiates between the two interneuronal populations. Transgene expression occurred in several subtypes of PG neurons, including those expressing calretinin, calbindin, GAD67, and tyrosine hydroxylase. These results suggest that a unique subset of SVZ precursor cells gives rise to PG, and not granule cells. The ability to express different transgenes within this subpopulation of neuronal precursors provides a powerful system to define the signals regulating the differentiation and survival of adult-generated neurons in the olfactory bulb.