Impact of Effective Global Tuberculosis Control on Health and Economic Outcomes in the United States.

Rationale: Most U.S. residents who develop tuberculosis (TB) were born abroad, and U.S. TB incidence is increasingly driven by infection risks in other countries.Objectives: To estimate the potential impact of effective global TB control on health and economic outcomes in the United States.Methods: We estimated outcomes using linked mathematical models of TB epidemiology in the United States and migrants' birth countries. A base-case scenario extrapolated country-specific TB incidence trends. We compared this with scenarios in which countries achieve 90% TB incidence reductions between 2015 and 2035, as targeted by the World Health Organization's End TB Strategy ("effective global TB control"). We also considered pessimistic scenarios of flat TB incidence trends in individual countries.Measurements and Main Results: We estimated TB cases, deaths, and costs and the total economic burden of TB in the United States. Compared with the base-case scenario, effective global TB control would avert 40,000 (95% uncertainty interval, 29,000-55,000) TB cases in the United States in 2020-2035. TB incidence rates in 2035 would be 43% (95% uncertainty interval, 34-54%) lower than in the base-case scenario, and 49% (95% uncertainty interval, 44-55%) lower than in 2020. Summed over 2020-2035, this represents 0.8 billion dollars (95% uncertainty interval, 0.6-1.0 billion dollars) in averted healthcare costs and $2.5 billion dollars (95% uncertainty interval, 1.7-3.6 billion dollars) in productivity gains. The total U.S. economic burden of TB (including the value of averted TB deaths) would be 21% (95% uncertainty interval, 16-28%) lower (18 billion dollars [95% uncertainty level, 8-32 billion dollars]).Conclusions: In addition to producing major health benefits for high-burden countries, strengthened efforts to achieve effective global TB control could produce substantial health and economic benefits for the United States.

Correction to: Systematic review and meta-analysis of tick-borne disease risk factors in residential yards, neighborhoods, and beyond.

Following publication of the original article [1], one of the authors, Dr. Sarah E. Bowden reported that at the time of the study she wasn't working for the Division of Global Migration and Quarantine, Centers for Disease Control, 1600 Clifton Road, Atlanta, GA 30329-4027, USA.

Systematic review and meta-analysis of tick-borne disease risk factors in residential yards, neighborhoods, and beyond.

BACKGROUND: Exposure to blacklegged ticks Ixodes scapularis that transmit pathogens is thought to occur peri-domestically. However, the locations where people most frequently encounter infected ticks are not well characterized, leading to mixed messages from public health officials about where risk is highest. METHODS: We conducted a systematic review and meta-analysis on spatial risk factors for tick-borne disease and tick bites in eastern North America. We examined three scales: the residential yard, the neighborhood surrounding (but not including) the yard, and outside the neighborhood. Nineteen eligible studies represented 2741 cases of tick-borne illness and 1447 tick bites. Using random effects models, we derived pooled odds ratio (OR) estimates. RESULTS: The meta-analysis revealed significant disease risk factors at the scale of the yard (OR 2.60 95% CI 1.96 - 3.46), the neighborhood (OR 4.08 95% CI 2.49 - 6.68), and outside the neighborhood (OR 2.03 95% CI 1.59 - 2.59). Although significant risk exists at each scale, neighborhood scale risk factors best explained disease exposure. Analysis of variance revealed risk at the neighborhood scale was 57% greater than risk at the yard scale and 101% greater than risk outside the neighborhood. CONCLUSIONS: This analysis emphasizes the importance of understanding and reducing tick-borne disease risk at the neighborhood scale. Risk-reducing interventions applied at each scale could be effective, but interventions applied at the neighborhood scale are most likely to protect human health. TRIAL REGISTRATION: The study was registered with PROSPERO: CRD42017079169 .

Rodent reservoirs of future zoonotic diseases.

The increasing frequency of zoonotic disease events underscores a need to develop forecasting tools toward a more preemptive approach to outbreak investigation. We apply machine learning to data describing the traits and zoonotic pathogen diversity of the most speciose group of mammals, the rodents, which also comprise a disproportionate number of zoonotic disease reservoirs. Our models predict reservoir status in this group with over 90% accuracy, identifying species with high probabilities of harboring undiscovered zoonotic pathogens based on trait profiles that may serve as rules of thumb to distinguish reservoirs from nonreservoir species. Key predictors of zoonotic reservoirs include biogeographical properties, such as range size, as well as intrinsic host traits associated with lifetime reproductive output. Predicted hotspots of novel rodent reservoir diversity occur in the Middle East and Central Asia and the Midwestern United States.

Overexpression of human CD38/ADP-ribosyl cyclase enhances acetylcholine-induced Ca2+ signalling in rodent NG108-15 neuroblastoma cells.

The role of cyclic ADP-ribose (cADPR) and its synthetic enzyme, CD38, as a downstream signal of muscarinic acetylcholine receptors (mAChRs) was examined in neuroblastoma cells expressing M1 mAChRs (NGM1). NGM1 cells were further transformed with both wild-type and mutant (C119K/C201E) human CD38. The dual transformed cells exhibited higher cADPR formation than ADPR production and elevated intracellular free Ca(2+) concentrations ([Ca(2+)](i)) in response to ACh. These phenotypes were analyzed in detail in a representative CD38 clone. The intracellular cADPR concentration by ACh application was significantly increased by CD38 overexpression. Digital image analysis by a confocal microscopy revealed that topographical distribution of the sites of Ca(2+) release was unchanged between control and overexpressed cells. These results indicate that cADPR is an intracellular messenger of Ca(2+) signalling, suggesting that CD38 can contribute to mAChR-cADPR signalling.

Undiscovered Bat Hosts of Filoviruses.

Ebola and other filoviruses pose significant public health and conservation threats by causing high mortality in primates, including humans. Preventing future outbreaks of ebolavirus depends on identifying wildlife reservoirs, but extraordinarily high biodiversity of potential hosts in temporally dynamic environments of equatorial Africa contributes to sporadic, unpredictable outbreaks that have hampered efforts to identify wild reservoirs for nearly 40 years. Using a machine learning algorithm, generalized boosted regression, we characterize potential filovirus-positive bat species with estimated 87% accuracy. Our model produces two specific outputs with immediate utility for guiding filovirus surveillance in the wild. First, we report a profile of intrinsic traits that discriminates hosts from non-hosts, providing a biological caricature of a filovirus-positive bat species. This profile emphasizes traits describing adult and neonate body sizes and rates of reproductive fitness, as well as species' geographic range overlap with regions of high mammalian diversity. Second, we identify several bat species ranked most likely to be filovirus-positive on the basis of intrinsic trait similarity with known filovirus-positive bats. New bat species predicted to be positive for filoviruses are widely distributed outside of equatorial Africa, with a majority of species overlapping in Southeast Asia. Taken together, these results spotlight several potential host species and geographical regions as high-probability targets for future filovirus surveillance.

Spread of white-nose syndrome on a network regulated by geography and climate.

Wildlife and plant diseases can reduce biodiversity, disrupt ecosystem services and threaten human health. Emerging pathogens have displayed a variety of spatial spread patterns due to differences in host ecology, including diffusive spread from an epicentre (West Nile virus), jump dispersal on a network (foot-and-mouth disease), or a combination of these (Sudden oak death). White-nose syndrome is a highly pathogenic infectious disease of bats currently spreading across North America. Understanding how bat ecology influences this spread is crucial to management of infected and vulnerable populations. Here we show that white-nose syndrome spread is not diffusive but rather mediated by patchily distributed habitat and large-scale gradients in winter climate. Simulations predict rapid expansion and infection of most counties with caves in the contiguous United States by winter 2105-2106. Our findings show the unique pattern of white-nose syndrome spread corresponds to ecological traits of the host and suggest hypotheses for transmission mechanisms acting at the local scale.

Regional differences in the association between land cover and West Nile virus disease incidence in humans in the United States.

West Nile virus (WNV) is generally considered to be an urban pathogen in the United States, but studies associating land cover and disease incidence, seroprevalence, or infection rate in humans, birds, domesticated and wild mammals, and mosquitoes report varying and sometimes contradictory results at an array of spatial extents. Human infection can provide insight about basic transmission activity; therefore, we analyzed data on the incidence of WNV disease in humans to obtain a comprehensive picture of how human disease and land cover type are associated across the United States. Human WNV disease incidence in Northeastern regions was positively associated with urban land covers, whereas incidence in the Western United States was positively associated with agricultural land covers. We suggest that these regional associations are explained by the geographic distributions of prominent WNV vectors: Culex pipiens complex (including Cx. pipiens and Cx. quinquefasciatus) in the Northeast and Cx. tarsalis in the Western United States.

Modulation of single channels underlying hippocampal L-type current enhancement by agonists depends on the permeant ion.

The influx of calcium (Ca(2+)) ions through L-type channels underlies many cellular processes, ranging from initiation of gene transcription to activation of Ca(2+)-activated potassium channels. L-type channels possess a diagnostic pharmacology, being enhanced by the dihydropyridine BAY K 8644 and benzoylpyrrole FPL 64176. It is assumed that the action of these compounds is independent of the ion conducted through the channel. In contrast to this assumption, modulation of L-type channel activity in acutely dissociated rat CA1 hippocampal neurons depended on the divalent ion identity. BAY K 8644 and FPL 64176 substantially increased single-channel open time only when barium (Ba(2+)) was the permeant ion. BAY K 8644 increased single-channel conductance when either Ba(2+) or Ca(2+) ions were the charge carrier, an effect not observed with FPL 64176. BAY K 8644 enhanced the whole cell L-type channel Ca(2+)- or Ba(2+)-carried current without a change in deactivation tail kinetics. In contrast, enhancement by FPL 64176 was associated with a dramatic slowing of deactivation kinetics only when Ba(2+) and not Ca(2+) was the charge carrier. Current activation was slowed by FPL 64176 with either charge carrier, an effect arising from a clustering of agonist-modified long-duration openings toward the end of the voltage step. These data indicate that agonists enhanced L-type current by distinct mechanisms dependent on the permeant ion, indicating that care must be considered when used as diagnostic tools.