Bats generate lower affinity but higher diversity antibody responses than those of mice, but pathogen-binding capacity increases if protein is restricted in their diet.

Bats are reservoirs of many zoonotic viruses that are fatal in humans but do not cause disease in bats. Moreover, bats generate low neutralizing antibody titers in response to experimental viral infection, although more robust antibody responses have been observed in wild-caught bats during times of food stress. Here, we compared the antibody titers and B cell receptor (BCR) diversity of Jamaican fruit bats (Artibeus jamaicensis; JFBs) and BALB/c mice generated in response to T-dependent and T-independent antigens. We then manipulated the diet of JFBs and challenged them with H18N11 influenza A-like virus or a replication incompetent Nipah virus VSV (Nipah-riVSV). Under standard housing conditions, JFBs generated a lower avidity antibody response and possessed more BCR mRNA diversity compared to BALB/c mice. However, withholding protein from JFBs improved serum neutralization in response to Nipah-riVSV and improved serum antibody titers specific to H18 but reduced BCR mRNA diversity.

Strategic Directions in Preventive Intervention Research to Advance Health Equity.

As commissioned by the Society for Prevention Research, this paper describes and illustrates strategic approaches for reducing health inequities and advancing health equity when adopting an equity-focused approach for applying prevention science evidence-based theory, methodologies, and practices. We introduce an ecosystemic framework as a guide for analyzing, designing, and planning innovative equity-focused evidence-based preventive interventions designed to attain intended health equity outcomes. To advance this process, we introduce a health equity statement for conducting integrative analyses of ecosystemic framework pathways, by describing the role of social determinants, mechanisms, and interventions as factors directly linked to specific health equity outcomes. As background, we present health equity constructs, theories, and research evidence which can inform the design and development of equity-focused intervention approaches. We also describe multi-level interventions that when coordinated can produce synergistic intervention effects across macro, meso, and micro ecological levels. Under this approach, we encourage prevention and implementation scientists to apply and extend these strategic directions in future research to increase our evidence-based knowledge and theory building. A general goal is to apply prevention science knowledge to design, widely disseminate, and implement culturally grounded interventions that incrementally attain specific HE outcomes and an intended HE goal. We conclude with recommendations for conducting equity-focused prevention science research, interventions, and training.

Self-reported Adverse Childhood Experiences Among Custodial Grandmothers: Frequencies, Patterns, and Correlates.

Given the scarce past research on custodial grandparents' early life circumstances, we investigated frequencies, patterns, and predictors of 14 adverse childhood experiences (ACEs) reported by 355 custodial grandmothers (CGMs). Predominant ACEs were bullying (54.6%), verbal abuse (51.5%), physical abuse (45.4%), and living with a substance abuser (41.1%). Only 11% of CGMs reported 0 ACEs, whereas 52.4% reported >4. Latent class analyses yielded three classes of ACE exposure: minimal (54.1%), physical/emotional abuse (25.9%), and complex (20.0%). Age was the only demographic factor related to ACE class, with the complex class being younger than the other two. MANCOVAs with age as a covariate revealed that different ACE profiles have unique impacts on CGMs' physical and psychological well-being. We conclude that ACEs are highly prevalent among CGMs and a serious public health concern. Future research addressing ACEs among CGMs is critical in order to support these caregivers and promote resilience in custodial grandfamilies.

Barriers and facilitators to hepatitis C screening and treatment for people with lived experience of homelessness: A mixed-methods systematic review.

BACKGROUND: People experiencing homelessness have an increased risk of hepatitis C virus (HCV) infection, with rates higher than the general population. However, their access to HCV diagnosis is limited and treatment uptake is low. OBJECTIVES: To identify and describe the barriers and facilitators for HCV screening and treatment for adults with lived experience of homelessness in highly developed countries. METHODS: Bibliographic databases (Embase, MEDLINE, CINAHL and SocINDEX) and grey literature (Google, EThOS, the Health Foundation, Social Care Online, the World Health Organisation, Shelter, Crisis and Pathway) were searched. Two reviewers independently screened and appraised all studies. The Critical Appraisal Skills Programme tool and the Joanna Briggs Institute checklist were used. The analysis involved a three-stage process: coding, theme generation and theme mapping under Penchansky and Thomas's modified access model. RESULTS: Twelve papers/reports were included in the review. Several interacting factors influence access of people with lived experience of homelessness to HCV testing and treatment. Some mirror those identified for the general population. The precarious conditions associated with the lived experience of homelessness along with the rigidity of hospital settings and lack of awareness emerged as dominant barriers. Flexibility, outreach, effective communication, tailoring and integration of services were found to be important facilitators. Evidence from Black, Asian and minority ethnic groups is limited. CONCLUSIONS: People experiencing homelessness face multiple barriers in accessing and completing HCV treatment, relating to both their lived experience and characteristics of health systems. Although some barriers are readily amenable to change, others are more difficult to modify. The facilitators identified could inform future targeted measures to improve HCV diagnosis and treatment for people experiencing homelessness. Research is warranted into successful models to promote screening, diagnosis and treatment. PATIENT OR PUBLIC CONTRIBUTION: Our team includes a peer advocate, a hepatology nurse and a community volunteer, all with significant experience in promoting and engaging in HCV care and outreach for people experiencing homelessness. They contributed to the protocol, interpretation and reporting of the review findings.

Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations.

Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C-H insertion processes demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity.

Temporal and spatial limitations in global surveillance for bat filoviruses and henipaviruses.

Sampling reservoir hosts over time and space is critical to detect epizootics, predict spillover and design interventions. However, because sampling is logistically difficult and expensive, researchers rarely perform spatio-temporal sampling of many reservoir hosts. Bats are reservoirs of many virulent zoonotic pathogens such as filoviruses and henipaviruses, yet the highly mobile nature of these animals has limited optimal sampling of bat populations. To quantify the frequency of temporal sampling and to characterize the geographical scope of bat virus research, we here collated data on filovirus and henipavirus prevalence and seroprevalence in wild bats. We used a phylogenetically controlled meta-analysis to next assess temporal and spatial variation in bat virus detection estimates. Our analysis shows that only one in four bat virus studies report data longitudinally, that sampling efforts cluster geographically (e.g. filovirus data are available across much of Africa and Asia but are absent from Latin America and Oceania), and that sampling designs and reporting practices may affect some viral detection estimates (e.g. filovirus seroprevalence). Within the limited number of longitudinal bat virus studies, we observed high heterogeneity in viral detection estimates that in turn reflected both spatial and temporal variation. This suggests that spatio-temporal sampling designs are important to understand how zoonotic viruses are maintained and spread within and across wild bat populations, which in turn could help predict and preempt risks of zoonotic viral spillover.

Examining Intervention Component Dosage Effects on Substance Use Initiation in the Strengthening Families Program: for Parents and Youth Ages 10-14.

Family-based prevention programs increasingly are being disseminated and can be effective for an array of adolescent problem behaviors, including substance use initiation. Yet, we continue to have little understanding of how and why these programs work. Increased specificity in our understanding of what components drive program effects can facilitate refinement of programs, with potential for greater impact at a lower cost. Using attendance data, previously coded intervention components, and a previously developed propensity model to adjust for potential bias, this study evaluated content component-specific dosage effects of the Strengthening Families Program: for Parents and Youth Ages 10-14 on three substance use initiation outcomes by grade 12. Results indicated that greater dosages of program content related to (a) parental monitoring and behavior management strategies and (b) promoting positive family relationships had potent and robust effects on reduction of risk for initiating drunkenness and marijuana use and (c) self-regulation and stress management had potent and robust effects on reduction of risk for initiating cigarette and marijuana use. Results indicate potential critical components within SFP 10-14 and offer a path forward for continuing work in efforts to optimize this widely disseminated program.

Copper-Mediated, Heterogeneous, Enantioselective Intramolecular Buchner Reactions of α-Diazoketones Using Continuous Flow Processing.

Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper-bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process.

Taming tosyl azide: the development of a scalable continuous diazo transfer process.

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including ß-ketoesters, ß-ketoamides, malonate esters and ß-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an α-diazocarbonyl in >98% purity without any column chromatography.

A Randomized Clinical Trial of Online Social Intelligence Training With Custodial Grandmothers.

BACKGROUND AND OBJECTIVES: In this study, we investigated the efficacy of a self-administered, online Social Intelligence Training (SIT) program aimed at enhancing psychological and relational well-being among a nationwide U.S. sample of custodial grandmothers. RESEARCH DESIGN AND METHODS: A two-arm randomized clinical trial (RCT) was conducted, where 349 grandmothers raising grandchildren aged 11-18 years were assigned to either SIT or an attention control condition (ACC). Participants self-completed online surveys at baseline and immediately postintervention, in addition to follow-ups at 3-, 6-, and 9-month postintervention. First-order latent difference score models were used to compare SIT to ACC, across all times of measurement, along key indicators of psychological and relational well-being on an intent-to-treat basis. RESULTS: Although SIT was largely superior to ACC at yielding positive results, it appears that it attenuated longitudinal declines that occurred among ACC participants. SIT also exerted stronger effects on relational than psychological outcomes, with perceived relations with grandchildren being the most positively affected. DISCUSSION AND IMPLICATIONS: Given that the historical time of this RCT unpredictably corresponded with the coronavirus disease 2019 pandemic, we suspect that SIT helped offset declines in psychological and relational well-being that are widely documented to have resulted from the pandemic. Our overall positive findings support future use of the inexpensive and easily delivered SIT program under normal environmental conditions, with the vulnerable and geographically disperse population of custodial grandmothers. CLINICAL TRIALS REGISTRATION NUMBER: NCT03239977.

Self-Reported Adverse Childhood Experiences and Risk for Internalizing and Externalizing Difficulties among Adolescent Custodial Grandchildren.

Despite custodial grandchildren's (CG) traumatic histories and risk for psychological difficulties, knowledge is scant regarding the frequencies, types, and consequences es of adverse childhood experiences (ACEs) they have encountered. We examined self-reported ACEs via online surveys with 342 CG (ages 12 to 18) who were recruited to participate in an RCT of a social intelligence training program. ACEs were assessed by 14 widely used items, and risk for internalizing (ID) and externalizing (ED) difficulties were measured using 80th percentile cut-offs on the Strengths and Difficulties Questionnaire. Classification and regression tree analyses included all 14 ACEs (along with CG gender and age) as predictors of ID and ED risk separately. Given possible comorbidity, analyses were run with and without the other risk type as a predictor. Less than 9% of CG self-reported no ACEs, 48.6% reported two to five ACEs, and 30.5 % reported ≥ 6. Irrespective of ED risk, bullying from peers strongly predicted ID risk. ED risk was peak among CG who also had risk for ID. Without ID risk as a predictor, ED risk was highest among CG who were emotionally abused, not lived with a substance abuser, and encountered neighborhood violence. The frequency and types of ACEs observed were alarmingly higher than those among the general population, suggesting that many CG have histories of trauma and household dysfunction. That a small number of ACEs among the 14 studied here were significant predictors of ID and ED risk challenges the widespread belief of a cumulative dose ACE effect.

Correction: Prioritizing surveillance of Nipah virus in India.

[This corrects the article DOI: 10.1371/journal.pntd.0007393.].

How substance use prevention research gets used in United States federal policy.

BACKGROUND AND AIMS: The growing body of research evidence on substance use and substance use disorder (SU/SUD) prevention could be leveraged to strengthen the intended impact of policies that address SU/SUD. The aim of the present study was to explore how research was used in United States federal legislation that emphasized SU/SUD prevention. DESIGN: Using a mixed-methods approach, we assessed whether the use of research predicted a bill's legislative progress. We randomly sampled 10 bills that represented different types of research keywords to examine how research was used in these bills, applying content analysis. SETTING: United States Congress. PARTICIPANTS/CASES: Federal legislation introduced between the 101st and the 114th Congresses (1989-2017; n = 1866). MEASUREMENTS: The quantitative outcome measures were bills' likelihood of passing out of committee and being enacted. Qualitative outcomes included the ways research was used in legislation. FINDINGS: Bills that used any research language were 2.2 times more likely to pass out of committee (OR = 2.18; 95% CI, 1.75, 2.72) and 82% more likely to be enacted (OR = 1.82; 95% CI, 1.23, 2.69) than bills not using research language. Bills using dissemination words were 57% more likely to pass out of committee (OR = 1.57; CI, 1.08, 2.28) and analysis words were 93% more likely (OR = 1.93; 95% CI, 1.51, 2.47) than bills not using dissemination or analysis words. Research was used to (i) define the problem to justify legislative action, (ii) address the problem by providing funding, and (iii) address the problem through industry regulations. However, there was a lack of research use that targets underlying risk and protective factors. CONCLUSIONS: In the US Congress, substance use and substance use disorder prevention bills that use research language appear to be more likely to progress in the legislative cycle than bills that do not, suggesting that legislation using research may be viewed as more credible.

Ecology, evolution and spillover of coronaviruses from bats.

In the past two decades, three coronaviruses with ancestral origins in bats have emerged and caused widespread outbreaks in humans, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the first SARS epidemic in 2002-2003, the appreciation of bats as key hosts of zoonotic coronaviruses has advanced rapidly. More than 4,000 coronavirus sequences from 14 bat families have been identified, yet the true diversity of bat coronaviruses is probably much greater. Given that bats are the likely evolutionary source for several human coronaviruses, including strains that cause mild upper respiratory tract disease, their role in historic and future pandemics requires ongoing investigation. We review and integrate information on bat-coronavirus interactions at the molecular, tissue, host and population levels. We identify critical gaps in knowledge of bat coronaviruses, which relate to spillover and pandemic risk, including the pathways to zoonotic spillover, the infection dynamics within bat reservoir hosts, the role of prior adaptation in intermediate hosts for zoonotic transmission and the viral genotypes or traits that predict zoonotic capacity and pandemic potential. Filling these knowledge gaps may help prevent the next pandemic.

Dirhodium Carboxylate Catalysts from 2-Fenchyloxy or 2-Menthyloxy Arylacetic Acids: Enantioselective C-H Insertion, Aromatic Addition and Oxonium Ylide Formation/Rearrangement.

A new class of dirhodium carboxylate catalysts have been designed and synthesized from 2-fenchyloxy or 2-menthyloxy arylacetic acids which display excellent enantioselectivity across a range of transformations of α-diazocarbonyl compounds. The catalysts were successfully applied to enantioselective C-H insertion reactions of aryldiazoacetates and α-diazo-ß-oxosulfones affording the respective products in up to 93 % ee with excellent trans diastereoselectivity in most cases. Furthermore, efficient desymmetrization in an intramolecular C-H insertion was achieved. In addition, these catalysts prove highly enantioselective for intramolecular aromatic addition with up to 88 % ee, and oxonium ylide formation and rearrangement with up to 74 % ee.

Identifying Suspect Bat Reservoirs of Emerging Infections.

Bats host a number of pathogens that cause severe disease and onward transmission in humans and domestic animals. Some of these pathogens, including henipaviruses and filoviruses, are considered a concern for future pandemics. There has been substantial effort to identify these viruses in bats. However, the reservoir hosts for Ebola virus are still unknown and henipaviruses are largely uncharacterized across their distribution. Identifying reservoir species is critical in understanding the viral ecology within these hosts and the conditions that lead to spillover. We collated surveillance data to identify taxonomic patterns in prevalence and seroprevalence and to assess sampling efforts across species. We systematically collected data on filovirus and henipavirus detections and used a machine-learning algorithm, phylofactorization, in order to search the bat phylogeny for cladistic patterns in filovirus and henipavirus infection, accounting for sampling efforts. Across sampled bat species, evidence for filovirus infection was widely dispersed across the sampled phylogeny. We found major gaps in filovirus sampling in bats, especially in Western Hemisphere species. Evidence for henipavirus infection was clustered within the Pteropodidae; however, no other clades have been as intensely sampled. The major predictor of filovirus and henipavirus exposure or infection was sampling effort. Based on these results, we recommend expanding surveillance for these pathogens across the bat phylogenetic tree.

Considering the child welfare system burden from opioid misuse: research priorities for estimating public costs.

The negative impact of opioids on those who misuse them has been widely documented. Despite significant spillover effects in the form of elevated rates of child maltreatment and child welfare system (CWS) involvement for children affected by parental opioid misuse, the public costs of opioid misuse to the CWS remain largely undocumented. This work seeks to understand the value and limitations of public data in estimating the costs of the opioid epidemic on the CWS. National data from federal sources are combined with best estimates of the association between opioid misuse and child services system utilization. The limitations of this work are explored, and future research priorities are outlined. Ultimately, this work illustrates the need to (1) improve data quality related to parental opioid misuse and CWS linkages; (2) better estimate the number of children and families coming into contact with the CWS as a result of parental opioid misuse; (3) improve predictions of CWS trajectories, including investigation, service provision, and foster care entry among this population; and (4) better estimate the CWS costs associated with patterns of system involvement resulting from parental opioid misuse. This information is crucial to ensuring the production of high-quality system involvement and cost projections related to the opioid crisis.

Percolation models of pathogen spillover.

Predicting pathogen spillover requires counting spillover events and aligning such counts with process-related covariates for each spillover event. How can we connect our analysis of spillover counts to simple, mechanistic models of pathogens jumping from reservoir hosts to recipient hosts? We illustrate how the pathways to pathogen spillover can be represented as a directed graph connecting reservoir hosts and recipient hosts and the number of spillover events modelled as a percolation of infectious units along that graph. Percolation models of pathogen spillover formalize popular intuition and management concepts for pathogen spillover, such as the inextricably multilevel nature of cross-species transmission, the impact of covariance between processes such as pathogen shedding and human susceptibility on spillover risk, and the assumptions under which the effect of a management intervention targeting one process, such as persistence of vectors, will translate to an equal effect on the overall spillover risk. Percolation models also link statistical analysis of spillover event datasets with a mechanistic model of spillover. Linear models, one might construct for process-specific parameters, such as the log-rate of shedding from one of several alternative reservoirs, yield a nonlinear model of the log-rate of spillover. The resulting nonlinearity is approximately piecewise linear with major impacts on statistical inferences of the importance of process-specific covariates such as vector density. We recommend that statistical analysis of spillover datasets use piecewise linear models, such as generalized additive models, regression clustering or ensembles of linear models, to capture the piecewise linearity expected from percolation models. We discuss the implications of our findings for predictions of spillover risk beyond the range of observed covariates, a major challenge of forecasting spillover risk in the Anthropocene. This article is part of the theme issue 'Dynamic and integrative approaches to understanding pathogen spillover'.

Prioritizing surveillance of Nipah virus in India.

The 2018 outbreak of Nipah virus in Kerala, India, highlights the need for global surveillance of henipaviruses in bats, which are the reservoir hosts for this and other viruses. Nipah virus, an emerging paramyxovirus in the genus Henipavirus, causes severe disease and stuttering chains of transmission in humans and is considered a potential pandemic threat. In May 2018, an outbreak of Nipah virus began in Kerala, > 1800 km from the sites of previous outbreaks in eastern India in 2001 and 2007. Twenty-three people were infected and 21 people died (16 deaths and 18 cases were laboratory confirmed). Initial surveillance focused on insectivorous bats (Megaderma spasma), whereas follow-up surveys within Kerala found evidence of Nipah virus in fruit bats (Pteropus medius). P. medius is the confirmed host in Bangladesh and is now a confirmed host in India. However, other bat species may also serve as reservoir hosts of henipaviruses. To inform surveillance of Nipah virus in bats, we reviewed and analyzed the published records of Nipah virus surveillance globally. We applied a trait-based machine learning approach to a subset of species that occur in Asia, Australia, and Oceana. In addition to seven species in Kerala that were previously identified as Nipah virus seropositive, we identified at least four bat species that, on the basis of trait similarity with known Nipah virus-seropositive species, have a relatively high likelihood of exposure to Nipah or Nipah-like viruses in India. These machine-learning approaches provide the first step in the sequence of studies required to assess the risk of Nipah virus spillover in India. Nipah virus surveillance not only within Kerala but also elsewhere in India would benefit from a research pipeline that included surveys of known and predicted reservoirs for serological evidence of past infection with Nipah virus (or cross reacting henipaviruses). Serosurveys should then be followed by longitudinal spatial and temporal studies to detect shedding and isolate virus from species with evidence of infection. Ecological studies will then be required to understand the dynamics governing prevalence and shedding in bats and the contacts that could pose a risk to public health.

Taxonomic patterns in the zoonotic potential of mammalian viruses.

Predicting and simplifying which pathogens may spill over from animals to humans is a major priority in infectious disease biology. Many efforts to determine which viruses are at risk of spillover use a subset of viral traits to find trait-based associations with spillover. We adapt a new method-phylofactorization-to identify not traits but lineages of viruses at risk of spilling over. Phylofactorization is used to partition the International Committee on Taxonomy of Viruses viral taxonomy based on non-human host range of viruses and whether there exists evidence the viruses have infected humans. We identify clades on a range of taxonomic levels with high or low propensities to spillover, thereby simplifying the classification of zoonotic potential of mammalian viruses. Phylofactorization by whether a virus is zoonotic yields many disjoint clades of viruses containing few to no representatives that have spilled over to humans. Phylofactorization by non-human host breadth yields several clades with significantly higher host breadth. We connect the phylogenetic factors above with life-histories of clades, revisit trait-based analyses, and illustrate how cladistic coarse-graining of zoonotic potential can refine trait-based analyses by illuminating clade-specific determinants of spillover risk.