Analysis of cell free DNA to predict outcome to bevacizumab therapy in colorectal cancer patients.

To predict outcome to combination bevacizumab (BVZ) therapy, we employed cell-free DNA (cfDNA) to determine chromosomal instability (CIN), nucleosome footprints (NF) and methylation profiles in metastatic colorectal cancer (mCRC) patients. Low-coverage whole-genome sequencing (LC-WGS) was performed on matched tumor and plasma samples, collected from 74 mCRC patients from the AC-ANGIOPREDICT Phase II trial (NCT01822444), and analysed for CIN and NFs. A validation cohort of plasma samples from the University Medical Center Mannheim (UMM) was similarly profiled. 61 AC-ANGIOPREDICT plasma samples collected before and following BVZ treatment were selected for targeted methylation sequencing. Using cfDNA CIN profiles, AC-ANGIOPREDICT samples were subtyped with 92.3% accuracy into low and high CIN clusters, with good concordance observed between matched plasma and tumor. Improved survival was observed in CIN-high patients. Plasma-based CIN clustering was validated in the UMM cohort. Methylation profiling identified differences in CIN-low vs. CIN high (AUC = 0.87). Moreover, significant methylation score decreases following BVZ was associated with improved outcome (p = 0.013). Analysis of CIN, NFs and methylation profiles from cfDNA in plasma samples facilitates stratification into CIN clusters which inform patient response to treatment.

Reservoir displacement by an invasive rodent reduces Lassa virus zoonotic spillover risk.

The black rat (Rattus rattus) is a globally invasive species that has been widely introduced across Africa. Within its invasive range in West Africa, R. rattus may compete with the native rodent Mastomys natalensis, the primary reservoir host of Lassa virus, a zoonotic pathogen that kills thousands annually. Here, we use rodent trapping data from Sierra Leone and Guinea to show that R. rattus presence reduces M. natalensis density within the human dwellings where Lassa virus exposure is most likely to occur. Further, we integrate infection data from M. natalensis to demonstrate that Lassa virus zoonotic spillover risk is lower at sites with R. rattus. While non-native species can have numerous negative effects on ecosystems, our results suggest that R. rattus invasion has the indirect benefit of decreasing zoonotic spillover of an endemic pathogen, with important implications for invasive species control across West Africa.

Validating the Revised Mating Effort Questionnaire.

The mating effort questionnaire (MEQ) is a multi-dimensional self-report instrument that captures factors reflecting individual effort in upgrading from a current partner, investment in a current partner, and mate seeking when not romantically paired. In the current studies, we sought to revise the MEQ so that it distinguishes among two facets of mate seeking-mate locating and mate attracting-to enable a more nuanced measurement and understanding of individual mating effort. Moreover, we developed additional items to better measure partner investment. In total, the number of items was increased from 12 to 26. In Study 1, exploratory factor analysis revealed that a four-factor solution, reflecting partner upgrading, mate locating, mate attracting, and partner investment, yielded the best fit. In Study 2, this structure was replicated using confirmatory factor analysis in an independent sample. Based on extant studies documenting the relationships between psychopathy, short-term mating effort, and sexual risk taking, a structural equation model (SEM) indicated that trait psychopathy positively predicted mate locating, mate attracting, and partner upgrading and negatively predicted partner investment. A separate SEM showed that partner upgrading positively predicted risky sexual behaviors, while partner upgrading and mate locating positively predicted acceptance of cosmetic surgery.

Longitudinal examination of alcohol demand and alcohol-related reinforcement as predictors of heavy drinking and adverse alcohol consequences in emerging adults.

BACKGROUND AND AIMS: Behavioral economic theory predicts that high alcohol demand and high proportionate alcohol-related reinforcement are important determinants of risky alcohol use in emerging adults, but the majority of research to date has been cross-sectional in nature. The present study investigated prospective and dynamic relationships between alcohol demand and proportionate alcohol-related reinforcement in relation to heavy drinking days and alcohol problems. DESIGN: Longitudinal cohort with assessments every 4 months for 20 months. SETTING: Ontario, Canada. PARTICIPANTS: Emerging adults reporting regular heavy episodic drinking (n = 636, Mage = 21.44; 55.8% female). MEASUREMENTS: Heavy drinking days (HDD; Daily Drinking Questionnaire), alcohol problems (Brief Young Adult Alcohol Consequences Questionnaire), alcohol demand (Alcohol Purchase Task) and proportionate alcohol-related reinforcement (Activity Level Questionnaire). FINDINGS: Linear mixed effects models revealed that behavioral economic indicators and alcohol-related outcomes significantly decreased over the study, consistent with 'aging out' of risky alcohol use. Random intercept cross-lagged panel models revealed significant between-person relationships, such that higher alcohol demand and alcohol-related reinforcement were positively associated with HDD and alcohol problems (random intercepts = 0.187-0.534, Ps < 0.01). Moreover, alcohol demand indicators (particularly the rate of change in elasticity of the demand curve, as measured by α, and the maximum expenditure, Omax) and proportionate alcohol-related reinforcement significantly forecasted changes in HDD at all time points (|ßs| = 0.063-0.103, Ps < 0.05) in cross-lagged relationships, with bidirectional associations noted for the rate of change in elasticity (ßs = -0.085 to -0.104, Ps < 0.01). Proportionate alcohol-related reinforcement also significantly forecasted changes in alcohol problems at all time points (ßs = 0.072-0.112, Ps < 0.01). CONCLUSIONS: Multiple behavioral economic indicators (demand elasticity, maximum expenditure and reinforcement ratio) forecast changes in heavy episodic drinking and alcohol problems over the course of emerging adulthood. These results further implicate alcohol demand and proportionate alcohol-related reinforcement as etiologically and developmentally important mechanisms in alcohol use trajectories.

Primary cardiac lymphoma presenting with cardiac tamponade and complete heart block: case report.

Background: Primary cardiac lymphoma (PCL) is rare and its presentation can be variable. Thorough workup of suspected PCL or other cardiac tumours typically incorporates a range of imaging techniques and laboratory investigations but ultimately diagnosis is confirmed by histological analysis of myocardial tissue. Case Summary: An 80-year-old Caucasian female presented with complete heart block and symptomatic cardiac tamponade. A pericardiocentesis was performed and a dual-chamber permanent pacemaker was implanted for the management of her complete heart block. Subsequently, a right atrial mass was discovered on imaging and the patient underwent endomyocardial biopsy of the mass. Histological analysis of the sample confirmed a primary cardiac lymphoma. The patient opted to forgo treatment with chemotherapy and died from her disease 1 month later. Discussion: Cardiac arrhythmias can occur in PCL due to infiltration of conduction pathways. Characterization of cardiac masses on various imaging modalities and laboratory tests guides diagnosis. Tissue diagnosis is required to confirm PCL. The location of a cardiac mass may present technical challenges when undertaking a biopsy, so the best approach to tissue sampling should be considered on an individual basis. Without treatment survival is less than one month but with modern chemoimmunotherapy five-year survival may exceed 50%.

Posttraumatic stress and delay discounting: a meta-analytic review.

Delay discounting-the extent to which individuals show a preference for smaller immediate rewards over larger delayed rewards-has been proposed as a transdiagnostic neurocognitive process across mental health conditions, but its examination in relation to posttraumatic stress disorder (PTSD) is comparatively recent. To assess the aggregated evidence for elevated delay discounting in relation to posttraumatic stress, we conducted a meta-analysis on existing empirical literature. Bibliographic searches identified 209 candidate articles, of which 13 articles with 14 independent effect sizes were eligible for meta-analysis, reflecting a combined sample size of N = 6897. Individual study designs included case-control (e.g. examination of differences in delay discounting between individuals with and without PTSD) and continuous association studies (e.g. relationship between posttraumatic stress symptom severity and delay discounting). In a combined analysis of all studies, the overall relationship was a small but statistically significant positive association between posttraumatic stress and delay discounting (r = .135, p < .0001). The same relationship was statistically significant for continuous association studies (r = .092, p = .027) and case-control designs (r = .179, p < .001). Evidence of publication bias was minimal. The included studies were limited in that many did not concurrently incorporate other psychiatric conditions in the analyses, leaving the specificity of the relationship to posttraumatic stress less clear. Nonetheless, these findings are broadly consistent with previous meta-analyses of delayed reward discounting in relation to other mental health conditions and provide further evidence for the transdiagnostic utility of this construct.

Spatio-temporal spread of Lassa virus and a new rodent host in the Mano River Union area, West Africa.

The spread of Lassa virus (LASV) in Guinea, Liberia and Sierra Leone, which together are named the Mano River Union (MRU) area, was examined phylogeographically. To provide a reliable evolutionary scenario, new rodent-derived, whole LASV sequences were included. These were generated by metatranscriptomic next-generation sequencing from rodents sampled between 2003 and 2020 in 21 localities of Guinea and Sierra Leone. An analysis was performed using BEAST to perform continuous phylogeographic inference and EvoLaps v36 to visualize spatio-temporal spread. LASV was identified as expected in its primary host reservoir, the Natal multimammate mouse (Mastomys natalensis), and also in two Guinean multimammate mice (Mastomys erythroleucus) in northern Sierra Leone and two rusty-bellied brush-furred mice (Lophuromys sikapusi) in southern Sierra Leone. This finding is consistent with the latter two species being secondary host reservoirs. The strains in these three species were very closely related in LASV lineage IV. Phylogenetic analysis indicated that the most recent common ancestor of lineage IV existed 316-374 years ago and revealed distinct, well-supported clades from Sierra Leone (Bo, Kabala and Kenema), Guinea (Faranah, Kissidougou-Guekedou and Macenta) and Liberia (Phebe-Ganta). The phylogeographic scenario suggests southern Guinea as the point of origin of LASV in the MRU area, with subsequent spread to towards Mali, Liberia and Sierra Leone at a mean speed of 1.6 to 1.1 km/year.

Correlates of cannabis use in a sample of mental health treatment-seeking Canadian armed forces members and veterans.

OBJECTIVE: Canadian Armed Forces (CAF) members and Veterans are more likely to experience mental health (MH) conditions, such as posttraumatic stress disorder (PTSD), than the general Canadian population. Previous research suggests that an increasing number of individuals are employing cannabis for MH symptom relief, despite a lack of robust evidence for its effectiveness in treating PTSD. This research aimed to: (1) describe the prevalence of current cannabis use among MH treatment-seeking CAF members and Veterans; and (2) estimate the association between current cannabis use and a number of sociodemographic, military, and MH-related characteristics. METHOD: Using cross-sectional intake data from 415 CAF members and Veterans attending a specialized outpatient MH clinic in Ontario, Canada, between January 2018 and December 2020, we estimated the proportion of CAF members and Veterans who reported current cannabis use for either medical or recreational purposes. We used multivariable logistic regression to estimate adjusted odds ratios for a number of sociodemographic, military, and MH-related variables and current cannabis use. RESULTS: Almost half of the study participants (n = 187; 45.1%) reported current cannabis use. Respondents who reported current cannabis use for medical purposes had a higher median daily dose than those who reported current cannabis use for recreational purposes. The multivariable logistic regression identified younger age, lower income, potentially hazardous alcohol use, and increased bodily pain as statistically significant correlates of current cannabis use among our MH treatment-seeking sample. PTSD severity, depressive severity, sleep quality, and suicide ideation were not statistically associated with current cannabis use. CONCLUSIONS: Almost half of our treatment-seeking sample reported current cannabis use for medical or recreational purposes, emphasizing the importance of screening MH treatment-seeking military members and Veterans for cannabis use prior to commencing treatment. Future research building upon this study could explore the potential impact of cannabis use on MH outcomes.

Changes in posttraumatic stress disorder symptom severity during the COVID-19 pandemic: Ten-wave findings from a longitudinal observational cohort study of community adults.

Few studies have examined changes in posttraumatic-stress disorder (PTSD) symptomatology across an extended time period during the COVID-19 pandemic. This study used a longitudinal cohort design to examine: (1) changes in overall PTSD symptoms and symptom clusters; (2) moderators of change; (3) the clinical significance of observed changes; and (4) correlates of clinically meaningful changes. Community adults (N = 1412) were assessed using the PTSD Checklist for DSM-5 (PCL-5) at 10 timepoints (October 2018 - April 2022). Changes in overall PCL-5 score and symptom clusters were substantially moderated by pre-pandemic clinical severity (i.e., above/below PCL-5 cut-off). Pre-pandemic non-clinical participants exhibited increases in overall scores, Cluster D (negative cognitions), and Cluster E (arousal), while clinically elevated participants exhibited decreases overall and in all clusters. Regarding clinical significance, 12% of pre-pandemic non-clinical participants exhibited clinically meaningful increases, and 4% exhibited decreases. Conversely, 42% of the pre-pandemic elevated group exhibited clinically meaningful decreases, while 6% exhibited increases. Pandemic impacts in numerous psychosocial domains were associated with clinically meaningful change. Collectively, these findings reveal substantively divergent trajectories by pre-pandemic severity and PTSD symptom cluster. The large proportion of pre-pandemic high-severity participants exhibiting sizable decreases was an unexpected notable observation.

Predicting the fine-scale spatial distribution of zoonotic reservoirs using computer vision.

Zoonotic diseases threaten human health worldwide and are often associated with anthropogenic disturbance. Predicting how disturbance influences spillover risk is critical for effective disease intervention but difficult to achieve at fine spatial scales. Here, we develop a method that learns the spatial distribution of a reservoir species from aerial imagery. Our approach uses neural networks to extract features of known or hypothesized importance from images. The spatial distribution of these features is then summarized and linked to spatially explicit reservoir presence/absence data using boosted regression trees. We demonstrate the utility of our method by applying it to the reservoir of Lassa virus, Mastomys natalensis, within the West African nations of Sierra Leone and Guinea. We show that, when trained using reservoir trapping data and publicly available aerial imagery, our framework learns relationships between environmental features and reservoir occurrence and accurately ranks areas according to the likelihood of reservoir presence.

Excluded and ashamed: Shame proneness interacts with social exclusion and testosterone reactivity to predict behavioral aggression.

Exclusion from social relationships is a painful experience that may threaten an individual's status and dominance. The steroid hormone testosterone, which fluctuates rapidly in response to such threats, may be implicated in subsequent behavioral action (e.g., aggressive or prosocial responses) that aims to protect or enhance one's status after exclusion. Past research, however, indicates that the link between acute changes in testosterone and behavior depend on context-relevant individual dispositions. In the context of social exclusion, an individual's level of shame proneness-characterized by a tendency to experience shame and to react submissively-is theoretically relevant to the testosterone-induced aggression relationship but has yet to be examined empirically. Here, men (n = 167) were randomly assigned to be socially included or excluded in the virtual ball-tossing game, Cyberball, after which aggressive behavior was examined using the Point Subtraction Aggression Paradigm (PSAP). Testosterone reactivity was measured via salivary hormone samples collected pre- and post-game. Moderated multiple regression analyses were run to examine the extent to which testosterone reactivity and shame proneness moderated the effect of Cyberball condition on aggression. Results revealed a significant two-way interaction between Cyberball condition and testosterone reactivity, as well as a three-way interaction including shame proneness. For individuals low in shame proneness, exclusion was associated with higher post-cyberball aggression among those who experienced a rise in testosterone but was associated with lower post-cyberball aggression among those who experienced a decrease in testosterone. For individuals high in shame proneness, however, exclusion did not meaningfully affect aggressive responses, regardless of whether they experienced an increase or decrease in testosterone. These findings extend our understanding of the moderating roles of context and disposition on the neuroendocrinology of aggression in social interaction.

Identifying the genetic basis of viral spillover using Lassa virus as a test case.

The rate at which zoonotic viruses spill over into the human population varies significantly over space and time. Remarkably, we do not yet know how much of this variation is attributable to genetic variation within viral populations. This gap in understanding arises because we lack methods of genetic analysis that can be easily applied to zoonotic viruses, where the number of available viral sequences is often limited, and opportunistic sampling introduces significant population stratification. Here, we explore the feasibility of using patterns of shared ancestry to correct for population stratification, enabling genome-wide association methods to identify genetic substitutions associated with spillover into the human population. Using a combination of phylogenetically structured simulations and Lassa virus sequences collected from humans and rodents in Sierra Leone, we demonstrate that existing methods do not fully correct for stratification, leading to elevated error rates. We also demonstrate, however, that the Type I error rate can be substantially reduced by confining the analysis to a less-stratified region of the phylogeny, even in an already-small dataset. Using this method, we detect two candidate single-nucleotide polymorphisms associated with spillover in the Lassa virus polymerase gene and provide generalized recommendations for the collection and analysis of zoonotic viruses.

Perspectives of Next-Generation Live-Attenuated Rift Valley Fever Vaccines for Animal and Human Use.

Live-attenuated Rift Valley fever (RVF) vaccines transiently replicate in the vaccinated host, thereby effectively initiating an innate and adaptive immune response. Rift Valley fever virus (RVFV)-specific neutralizing antibodies are considered the main correlate of protection. Vaccination with classical live-attenuated RVF vaccines during gestation in livestock has been associated with fetal malformations, stillbirths, and fetal demise. Facilitated by an increased understanding of the RVFV infection and replication cycle and availability of reverse genetics systems, novel rationally-designed live-attenuated candidate RVF vaccines with improved safety profiles have been developed. Several of these experimental vaccines are currently advancing beyond the proof-of-concept phase and are being evaluated for application in both animals and humans. We here provide perspectives on some of these next-generation live-attenuated RVF vaccines and highlight the opportunities and challenges of these approaches to improve global health.

Breast cancer outcomes in a private hospital appear better than national outcomes in a country with a mixed public/private healthcare model.

BACKGROUND: Ireland has a mixed model of healthcare delivery with a public healthcare system funded by general taxation and a large private healthcare insurance system, covering 43% of the population in 2012 and 2016. We set out to examine disparities in outcomes among patients with breast cancer treated in a private hospital compared to national outcomes over a comparable period. METHODS: Medical records of patients diagnosed with early (Stage 1-3 as per AJCC version 5) breast cancer between 2010 and 2015 at Bon Secours Hospital, Cork, Ireland were reviewed. Staging was confirmed and 5-year disease specific survival (DSS) and overall survival (OS) were calculated. DSS was compared to 5-year net survival (NS) figures from the National Cancer Registry of Ireland (NCRI) for a comparable period (2010-2014). RESULTS: DSS (Bon Secours) and NS (NCRI) are summarized in Table 5 and Fig. 2. 5-year survival figures are numerically higher in the private hospital compared with national data for individual stage. Taking stages 1 to 3 combined, the 95% confidence intervals do not cross, indicating statistical significance. CONCLUSIONS: We found evidence of superior outcomes in patients with early breast cancer treated at a private hospital compared with national outcome figures. This was demonstrated in 'all comers' (stages 1-3 combined), and particularly in patients with stage 3 breast cancer. Potential reasons for this disparity include differences in socioeconomic status, health-seeking behaviours and/or underlying health status between the two populations included. Differences in extent or timeliness of access to therapies may also contribute.

One Health timeliness metrics to track and evaluate outbreak response reporting: A scoping review.

Background: As the global population soars, human behaviours are increasing the risk of epidemics. Objective performance evaluation of outbreak responses requires that metrics of timeliness, or speed in response time, be recorded and reported. We sought to evaluate how timeliness data are being conveyed for multisectoral outbreaks and make recommendations on how One Health metrics can be used to improve response success. Methods: We conducted a scoping review of outbreaks reported January 1, 2010- March 15, 2020, in organizational reports and peer-reviewed literature on PubMed and Embase databases. We tracked 11 outbreak milestones and calculated timeliness metrics, the median time in days, between the following: 1) Predict; 2) Prevent; 3) Start; 4) Detect; 5) Notify; 6) Verify; 7) Diagnostic; 8) Respond; 9) Communication; 10) End; and 11) After-Action Review. Findings: We identified 26783 outbreak reports, 1014 of which involved more than just the human health sector. Only six of the eleven milestones were mentioned in >50% of reports. The time between most milestones was on average shorter for outbreaks reporting both Predict (alert of a potential outbreak) and Prevent (response to predictive alert) events. Interpretation: Tracking progress in timeliness during outbreaks can focus efforts to prevent outbreaks from evolving into epidemics or pandemics. Response to predictive alerts demonstrated improved expediency in time to most milestones. We recommend the adoption of universally defined One Health outbreak milestones, including After Action Review, such that timeliness metrics can be used to assess outbreak response improvements over time. Funding: This study was made possible by the United States Agency for International Development's One Health Workforce-Next Generation Project (Cooperative Agreement 7200AA19CA00018).

Predicting the potential for zoonotic transmission and host associations for novel viruses.

Host-virus associations have co-evolved under ecological and evolutionary selection pressures that shape cross-species transmission and spillover to humans. Observed virus-host associations provide relevant context for newly discovered wildlife viruses to assess knowledge gaps in host-range and estimate pathways for potential human infection. Using models to predict virus-host networks, we predicted the likelihood of humans as hosts for 513 newly discovered viruses detected by large-scale wildlife surveillance at high-risk animal-human interfaces in Africa, Asia, and Latin America. Predictions indicated that novel coronaviruses are likely to infect a greater number of host species than viruses from other families. Our models further characterize novel viruses through prioritization scores and directly inform surveillance targets to identify host ranges for newly discovered viruses.

Relatively rapid effects of testosterone on men's ratings of female attractiveness depend on relationship status and the attractiveness of stimulus faces.

Attractiveness judgements influence desires to initiate and maintain romantic relationships. Testosterone also predicts relationship initiation and maintenance; such effects may be driven by the hormone's modulation of attractiveness judgements, but no studies have investigated causal (and situation-dependent) effects of the hormone on these judgements. Using a placebo-controlled cross-over design, our preregistered analyses revealed order- and relationship- dependent effects: single heterosexual men judged the women as more appealing when testosterone was administered first (and placebo second), but marginally less appealing when placebo was administered first (and testosterone second). In a more complex model incorporating the women's attractiveness (as rated by an independent set of observers), however, we show that testosterone increases the appeal of women -but this effect depends upon the men's relationship status and the women's attractiveness. In partnered men (n = 53) who tend to derogate attractive alternatives (by rating them as less appealing), testosterone countered this effect, boosting the appeal of these attractive alternatives. In single men (n = 53), conversely, testosterone increased the appeal of low-attractive women. These differential effects highlight the possibility of a newly discovered mechanism whereby testosterone promotes male sexual reproduction through different routes depending on relationship status, promoting partner up- rather than down-grading when partnered and reducing choosiness when single. Further, such effects were relatively rapid [within 85 (±5) minutes], suggesting a potential non-genomic mechanism of action.

Genome Sequences of Five Arenaviruses from Pygmy Mice (Mus minutoides) in Sierra Leone.

The genome sequences of five strains of a mammarenavirus were assembled from metagenomic data from pygmy mice (Mus minutoides) captured in Sierra Leone. The nearest fully sequenced relatives of this virus, which was named Seli virus, are lymphocytic choriomeningitis virus, Lunk virus, and Ryukyu virus.

Gut microbiota-drug interactions in cancer pharmacotherapies: implications for efficacy and adverse effects.

INTRODUCTION: The gut microbiota is involved in host physiology and health. Reciprocal microbiota-drug interactions are increasingly recognized as underlying some individual differences in therapy response and adverse events. Cancer pharmacotherapies are characterized by a high degree of interpatient variability in efficacy and side effect profile and recently, the microbiota has emerged as a factor that may underlie these differences. AREAS COVERED: The effects of cancer pharmacotherapy on microbiota composition and function are reviewed with consideration of the relationship between baseline microbiota composition, microbiota modification, antibiotics exposure, and cancer therapy efficacy. We assess the evidence implicating the microbiota in cancer therapy-related adverse events including impaired gut function, cognition, and pain perception. Finally, potential mechanisms underlying microbiota-cancer drug interactions are described, including direct microbial metabolism, and microbial modulation of liver metabolism and immune function. This review focused on preclinical and clinical studies conducted in the last 5 years. EXPERT OPINION: Preclinical and clinical research supports a role for baseline microbiota in cancer therapy efficacy, with emerging evidence that the microbiota modification may assist in side effect management. Future efforts should focus on exploiting this knowledge toward the development of microbiota-targeted therapies. Finally, a focus on specific drug-microbiota-cancer interactions is warranted.