Is regulation preventing the development of therapeutics that may prevent future coronavirus pandemics?

In the last century, hundreds of new emerging infectious diseases (EIDs) have arisen in human populations most of which originate from wild animals as zoonoses [1]. The recent surge of zoonotic EIDs in human populations is driven by a constellation of socioeconomic factors including human population growth, eroding public health infrastructures, changes in land use and agriculture and ease of global travel. HIV, Ebola virus, avian influenza (H5N1, H7N9, etc.), severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are but a few recent examples of highly virulent, zoonotic viral EIDs that have catastrophically affected global economies and public health [2]. Geopolitical flux since the 1990s and the potential for weaponizing EIDs provoked the creation of myriad policies aimed at protecting the USA from bioterrorist threats and the accidental release of potential pandemic pathogens from laboratories. Are these policies effective? Are they impacting countermeasure development for current and future EIDs? How are they shaping the direction of individual research programs, the recruitment of new investigators and the stability of impacted fields? Below, we discuss our experiences in developing therapeutics against SARS-, MERS- and zoonotic CoV in an ever changing regulatory environment

Health effects in fish of long-term exposure to effluents from wastewater treatment works

The effects of simple mixtures of chemicals, with similar mechanisms of action, can be predicted using the concentration addition model (CA). The ability of this model to predict the estrogenic effects of more complex mixtures such as effluent discharges, however, has yet to be established. Effluents from 43 U.K. wastewater treatment works were analyzed for the presence of the principal estrogenic chemical contaminants, estradiol, estrone, ethinylestradiol, and nonylphenol. The measured concentrations were used to predict the estrogenic activity of each effluent, employing the model of CA, based on the relative potencies of the individual chemicals in an in vitro recombinant yeast estrogen screen (rYES) and a short-term (14-day) in vivo rainbow trout vitellogenin induction assay. Based on the measured concentrations of the four chemicals in the effluents and their relative potencies in each assay, the calculated in vitro and in vivo responses compared well and ranged between 3.5 and 87 ng/L of estradiol equivalents (E2 EQ) for the different effluents. In the rYES, however, the measured E2 EQ concentrations in the effluents ranged between 0.65 and 43 ng E2 EQ/L, and they varied against those predicted by the CA model. Deviations in the estimation of the estrogenic potency of the effluents by the CA model, compared with the measured responses in the rYES, are likely to have resulted from inaccuracies associated with the measurement of the chemicals in the extracts derived from the complex effluents. Such deviations could also result as a consequence of interactions between chemicals present in the extracts that disrupted the activation of the estrogen response elements in the rYES. E2 EQ concentrations derived from the vitellogenic response in fathead minnows exposed to a series of effluent dilutions were highly comparable with the E2 EQ concentrations derived from assessments of the estrogenic potency of these dilutions in the rYES. Together these data support the use of bioassays for determining the estrogenic potency of WwTW effluents, and they highlight the associated problems for modeling approaches that are reliant on measured concentrations of estrogenic chemicals

Escape from Human Monoclonal Antibody Neutralization Affects In Vitro and In Vivo Fitness of Severe Acute Respiratory Syndrome Coronavirus

Severe Acute Respiratory Syndrome (SARS) emerged as a human disease in 2002 and detailed phylogenetic analysis and epidemiological studies have suggested that the SARS-Coronavirus (SARS-CoV) originated from animals. The Spike (S) glycoprotein has been identified as a major target of protective immunity and contains at least three regions that are targeted by neutralizing antibodies in the S1 and S2 domains. We previously characterized a panel of neutralizing human monoclonal antibodies (MAbs) but the majority of epitopes recognized by the MAbs remained unknown

Facility-level characteristics associated with family planning and child immunization services integration in urban areas of Nigeria: a longitudinal analysis

Background: Unmet need for postpartum contraception is high. Integration of family planning with routine child immunization services may help to satisfy unmet need. However, evidence about the determinants and effects of integration has been inconsistent, and more evidence is required to ascertain whether and how to invest in integration. In this study, facility-level family planning and immunization integration index scores are used to: (1) determine whether integration changes over time and (2) identify whether facility-level characteristics, including exposure to the Nigerian Urban Reproductive Health Initiative (NURHI), are associated with integration across facilities in six urban areas of Nigeria. Methods: This study utilizes health facility data collected at baseline (n = 400) and endline (n = 385) for the NURHI impact evaluation. Difference-in-differences models estimate the associations between facility-level characteristics, including exposure to NURHI, and Provider and Facility Integration Index scores. The two outcome measures, Provider and Facility Integration Index scores, reflect attributes that support integrated service delivery. These indexes, which range from 0 (low) to 10 (high), were constructed using principal component analysis. Scores were calculated for each facility. Independent variables are (1) time period, (2) whether the facility received the NURHI intervention, and (3) additional facility-level characteristics. Results: Within intervention facilities, mean Provider Integration Index scores were 6.46 at baseline and 6.79 at endline; mean Facility Integration Index scores were 7.16 (baseline) and 7.36 (endline). Within non-intervention facilities, mean Provider Integration Index scores were 5.01 at baseline and 6.25 at endline; mean Facility Integration Index scores were 5.83 (baseline) and 6.12 (endline). Provider Integration Index scores increased significantly (p = 0.00) among non-intervention facilities. Facility Integration Index scores did not increase significantly in either group. Results identify facility-level characteristics associated with higher levels of integration, including smaller family planning client load, family planning training among providers, and public facility ownership. Exposure to NURHI was not associated with integration index scores. Conclusion: Programs aiming to increase integration of family planning and immunization services should monitor and provide targeted support for the implementation of a well-defined integration strategy that considers the influence of facility characteristics and concurrent initiatives

Development of integration indexes to determine the extent of family planning and child immunization services integration in health facilities in urban areas of Nigeria

Background: Integrating family planning into child immunization services may address unmet need for contraception by offering family planning information and services to postpartum women during routine child immunization visits. However, policies and programs promoting integration are often based on insubstantial or conflicting evidence about its effects on service delivery and health outcomes. While integration models vary, many studies measure integration as binary (a facility is integrated or not) rather than a multidimensional and varying continuum. It is thus challenging to ascertain the determinants and effects of integrated service delivery. This study creates Facility and Provider Integration Indexes, which measure capacity to support integrated family planning and child immunization services and applies them to analyze the extent of integration across 400 health facilities. Methods: This study utilizes cross-sectional health facility (N = 400; 58% hospitals, 42% primary healthcare centers) and healthcare provider (N = 1479) survey data that were collected in six urban areas of Nigeria for the impact evaluation of the Nigerian Urban Reproductive Health Initiative. Principal Component Analysis was used to develop Provider and Facility Integration Indexes that estimate the extent of integration in these health facilities. The Provider Integration Index measures provider skills and practices that support integrated service delivery while the Facility Integration Index measures facility norms that support integrated service delivery. Index scores range from zero (low) to ten (high). Results: Mean Provider Integration Index score is 5.42 (SD 3.10), and mean Facility Integration Index score is 6.22 (SD 2.72). Twenty-three percent of facilities were classified as having low Provider Integration scores, 32% as medium, and 45% as high. Fourteen percent of facilities were classified as having low Facility Integration scores, 38% as medium, and 48% as high. Conclusion: Many facilities in our sample have achieved high levels of integration, while many others have not. Results suggest that using more nuanced measures of integration may (a) more accurately reflect true variation in integration within and across health facilities, (b) enable more precise measurement of the determinants or effects of integration, and (c) provide more tailored, actionable information about how best to improve integration. Overall, results reinforce the importance of utilizing more nuanced measures of facility-level integration

Goal-seeking compresses neural codes for space in the human hippocampus and orbitofrontal cortex

Humans can navigate flexibly to meet their goals. Here, we asked how the neural representation of allocentric space is distorted by goal-directed behavior. Participants navigated an agent to two successive goal locations in a grid world environment comprising four interlinked rooms, with a contextual cue indicating the conditional dependence of one goal location on another. Examining the neural geometry by which room and context were encoded in fMRI signals, we found that map-like representations of the environment emerged in both hippocampus and neocortex. Cognitive maps in hippocampus and orbitofrontal cortices were compressed so that locations cued as goals were coded together in neural state space, and these distortions predicted successful learning. This effect was captured by a computational model in which current and prospective locations are jointly encoded in a place code, providing a theory of how goals warp the neural representation of space in macroscopic neural signals.</p

Goal-seeking compresses neural codes for space in the human hippocampus and orbitofrontal cortex

Humans can navigate flexibly to meet their goals. Here, we asked how the neural representation of allocentric space is distorted by goal-directed behavior. Participants navigated an agent to two successive goal locations in a grid world environment comprising four interlinked rooms, with a contextual cue indicating the conditional dependence of one goal location on another. Examining the neural geometry by which room and context were encoded in fMRI signals, we found that map-like representations of the environment emerged in both hippocampus and neocortex. Cognitive maps in hippocampus and orbitofrontal cortices were compressed so that locations cued as goals were coded together in neural state space, and these distortions predicted successful learning. This effect was captured by a computational model in which current and prospective locations are jointly encoded in a place code, providing a theory of how goals warp the neural representation of space in macroscopic neural signals