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Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7-10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2.

IntroductionPromoting smoking cessation is a global public health priority. E-cigarettes are increasingly being used by individuals to try quitting smoking. Identifying sources and types of information available to adults who are trying to quit, and the impact of this information during a quit attempt, is critical to augment the potential public health benefit of e-cigarettes for reducing cigarette smoking.MethodsUS adults (N = 857) who reported using e-cigarettes in a recent smoking cessation attempt completed an anonymous, cross sectional, online survey. We examined sources of information and type of information received when using e-cigarettes to quit smoking and their associations with the duration of abstinence achieved.ResultsThe two most commonly reported information sources were friends (43.9%) and the internet (35.2%), while 14.0% received information from a healthcare provider. People received information on type of device (48.5%), flavor (46.3%), and nicotine concentration (43.6%). More people received information about gradually switching from smoking to vaping (46.7%) than abruptly switching (30.2%). Obtaining information from healthcare providers (β (SE) = 0.16 (0.08), p = 0.04), getting information about abruptly switching to e-cigarettes (β (SE) = 0.14 (0.06), p = 0.01) and what nicotine concentrations to use (β (SE) = 0.18 (0.05), p = 0.03) were associated with longer quit durations.ConclusionsAmidst the growing popularity of e-cigarettes use for quitting smoking, our results highlight common sources of information and types of information received by individuals. Few people received information from healthcare providers indicating a gap in cessation support that can be filled. Providing information about immediate switching to e-cigarettes and nicotine concentrations to use may help in increasing quit rates and duration.

Mantle cell lymphoma (MCL) has a poor prognosis and high relapse rates despite current therapies, necessitating novel treatment regimens. Inhibition of SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas. Additionally, previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin's lymphoma patients, suggesting SRC-3 may play a role in the progression of B cell lymphoma. This study aimed to investigate novel SRC-3 inhibitors, SI-10 and SI-12, in mantle cell lymphoma. The cytotoxic effects of SI-10 and SI-12 were evaluated in vitro and demonstrated dose-dependent cytotoxicity in a panel of MCL cell lines. The in vivo efficacy of SI-10 was confirmed in two ibrutinib-resistant models: an immunocompetent disseminated A20 mouse model of B-cell lymphoma and a human PDX model of MCL. Notably, SI-10 treatment also resulted in a significant extension of survival in vivo with low toxicity in both ibrutinib-resistant murine models. We have investigated SI-10 as a novel anti-lymphoma compound via the inhibition of SRC-3 activity. These findings indicate that targeting SRC-3 should be investigated in combination with current clinical therapeutics as a novel strategy to expand the therapeutic index and to improve lymphoma outcomes.

A healthy gastrointestinal (GI) tract with a properly established microbiota is necessary for a foal to develop into a healthy weanling. A foal's health can be critically impacted by aberrations in the microbiome such as with diarrhea which can cause great morbidity and mortality in foals. In this study, we hypothesized that gut establishment in the foal transitioning from a diet of milk to a diet of grain, forage, and pasture would be detectable through analyses of the fecal microbiotas. Fecal samples from 37 sets of foals and mares were collected at multiple time points ranging from birth to weaning. Bacterial DNA was isolated from the samples, and the V4 domain of bacterial 16S rRNA genes were amplified via polymerase chain reaction. Next generation sequencing was then performed on the resulting amplicons, and analyses were performed to characterize the microbiome as well as the relative abundance of microbiota present. We found that bacterial population compositions followed a pattern throughout the early life of the foal in an age-dependent manner. As foals transitioned from milk consumption to a forage and grain diet, there were recognizable changes in fecal microbial compositions from initial populations predominant in the ability to metabolize milk to populations capable of utilizing fibrous plant material. We were also able to recognize differences in microbial populations amongst diarrheic foals as well as microbial population differences associated with differences in management styles between facilities. Future efforts will gauge the effects of lesser abundant bacterial populations that could also be essential to GI health, as well as to determine how associations between microbial population profiles and animal management practices can be used to inform strategies for improving upon the health and growth of horses overall.

IntroductionAdolescent girls and young women (AGYW) face barriers in accessing clinic-based HIV pre-exposure prophylaxis (PrEP) services and community-based models are a proposed alternative. Evidence from such models, however, is limited. We evaluated PrEP service coverage, uptake, and early persistence among AGYW receiving services through community and hybrid models in Namibia.MethodsWe analyzed routine data for AGYW aged 15-24 who initiated PrEP within HIV prevention programming. PrEP was delivered via three models: community-concierge (fully community-based services with individually-tailored refill locations), community-fixed (community-based initiation and refills delivered by community providers on a set schedule at fixed sites), and hybrid community-clinic (community-based initiation and referral to clinics for refills delivered by clinic providers). We examined proportions of AGYW engaged in services along a programmatic PrEP cascade, overall and by model, and assessed factors associated with PrEP uptake and early persistence (refill within 15-44 days after initiation) using multivariable generalized estimating equations.ResultsOver 10-months, 7593 AGYW participated in HIV prevention programming. Of these, 7516 (99.0%) received PrEP education, 6105 (81.2%) received HIV testing services, 6035 (98.9%) tested HIV-negative, and 2225 (36.9%) initiated PrEP. Of the 2047 AGYW expected for PrEP refill during the study period, 254 (12.4%) persisted with PrEP one-month after initiation. Structural and behavioral HIV risk factors including early school dropout, food insecurity, inconsistent condom use, and transactional sex were associated with PrEP uptake. AGYW who delayed starting PrEP were 2.89 times more likely to persist (95% confidence interval (CI): 1.52-5.46) and those receiving services via the community-concierge model were 8.7 times (95% CI: 5.44-13.9) more likely to persist (compared to the hybrid model).ConclusionCommunity-based models of PrEP service delivery to AGYW can achieve high PrEP education and HIV testing coverage and moderate PrEP uptake. AGYW-centered approaches to delivering PrEP refills can promote higher persistence.

IntroductionClinical trials evaluating the effectiveness of falls prevention interventions for people with Multiple Sclerosis (MS), Parkinson's Disease (PD) and stroke measure heterogeneous outcomes, often omitting those meaningful to patients. A core outcome set (COS) is a standardised set of outcomes that should be assessed in all trials within a research area. The aim of this study was to develop a COS for evaluating mixed-diagnosis falls prevention interventions for people with MS, PD and stroke in non-acute and community settings, with input from relevant stakeholder groups.MethodsPreviously published research undertaken by the team, including a qualitative study with 20 patients and a review of the literature, were used to derive a longlist of potential outcomes. Outcomes were prioritised for inclusion in the COS using a three-round online Delphi survey. A multi-stakeholder, consensus meeting was conducted to agree upon the final COS and to provide a recommendation for a single outcome measure for each outcome in the COS.ResultsForty-eight participants were recruited across four stakeholder groups (researchers, patients, clinicians, and service-planners/policymakers). A total of 42 participants (87.5%) completed all three rounds of the surveys. Sixty-two outcomes were considered for inclusion in the COS throughout the Delphi process. A total of 15 participants attended the consensus meeting where they agreed upon the final COS and accompanying measurement instruments: fall incidence, injurious fall incidence, quality of life, falls self-efficacy, fear of falling, activity curtailment due to fear of falling, and cost-effectiveness. Attendees at the consensus meeting recommended that the proposed mechanism of impact of an intervention is considered when selecting additional outcomes outside of those in the COS to assess.ConclusionsThis study identified a COS for evaluating the effectiveness of mixed-diagnosis falls prevention interventions for people with MS, PD and stroke. It is recommended that this COS and accompanying measurement instruments be used in all future trials in this research area so that findings can be combined and compared.

AimTo identify and systematically review current scholarship on talent management of international nurses in healthcare organizations.BackgroundAs nurse shortages persistently pose challenges for healthcare organizations globally, one of the primary strategies employed to address these shortages is employment of international nurses. To date little has been done to systematically review and collate contemporary research on talent management of this strategically important cohort. Talent management is a holistic construct that can support healthcare organizations to attract, develop, motivate, and retain talented employees to drive organizational performance. This systematic review isolates, appraises and collates available evidence on talent management practices for international nurses.Study designSystematic literature review.Data sourcesSearches of PubMed, EBSCO and Scopus were made covering literature from 2012-2022.Review methodsThis study followed Cochrane protocol for Systematic Reviews and key search terms were developed in consultation with University of Limerick library. As a key aim of the review was to provide evidence for the development of effective talent management practices, only peer-reviewed academic papers and empirical studies were included. Initial articles screening was conducted by two reviewers and full articles review was conducted by the entire research team. Findings were combined in a data extraction template for further analysis.ResultsThis review includes 62 articles thematically analysed under the headings recruitment and selection, retention and turnover, career progression, professional development, discrimination and racism, culture and communication.ConclusionNo articles were found that directly address talent management for international nurses. Although there are studies that address aspects of talent management independently, more research is required on talent management as a holistic process for international nurses to inform evidence-based practice.ImpactThis research emphasizes the importance of talent management for retention of international nurses in healthcare settings. It provides a knowledge base for healthcare organisations to enhance employee retention and ensure quality care for patients, as well as setting the foundation for future studies in this area.

Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7–10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Introduction: Promoting smoking cessation is a global public health priority. E-cigarettes are increasingly being used by individuals to try quitting smoking. Identifying sources and types of information available to adults who are trying to quit, and the impact of this information during a quit attempt, is critical to augment the potential public health benefit of e-cigarettes for reducing cigarette smoking. Methods: US adults (N = 857) who reported using e-cigarettes in a recent smoking cessation attempt completed an anonymous, cross sectional, online survey. We examined sources of information and type of information received when using e-cigarettes to quit smoking and their associations with the duration of abstinence achieved. Results: The two most commonly reported information sources were friends (43.9%) and the internet (35.2%), while 14.0% received information from a healthcare provider. People received information on type of device (48.5%), flavor (46.3%), and nicotine concentration (43.6%). More people received information about gradually switching from smoking to vaping (46.7%) than abruptly switching (30.2%). Obtaining information from healthcare providers (β (SE) = 0.16 (0.08), p = 0.04), getting information about abruptly switching to e-cigarettes (β (SE) = 0.14 (0.06), p = 0.01) and what nicotine concentrations to use (β (SE) = 0.18 (0.05), p = 0.03) were associated with longer quit durations. Conclusions: Amidst the growing popularity of e-cigarettes use for quitting smoking, our results highlight common sources of information and types of information received by individuals. Few people received information from healthcare providers indicating a gap in cessation support that can be filled. Providing information about immediate switching to e-cigarettes and nicotine concentrations to use may help in increasing quit rates and duration. [ABSTRACT FROM AUTHOR]

This paper details a protocol for a systematic review that will be used to identify, critically appraise, and synthesize current academic evidence relating talent management practices for internationally trained nurses in healthcare organizations. Databases used in the search will include CINAHL with full text (EBSCOhost), PubMED, PsycINFO, Embase, Business Source Complete, Academic Source Complete, Web of Science, and Medline. Searches are limited to studies in English. Based on receiving funding approval in May this review will systematically search all materials in databases up until 2022, with predetermined search terms. All studies will be screened based on specific criteria and predetermined search terms using the Boolean terminology. Risk of any bias will be considered and assessed using the checklist provided by the National Institute of Health and Clinical excellence. Two assessors will review the findings using convergence and any disagreement will be settled by a third-party reviewer. The systematic review will produce a synthesis of the data related to talent management practices for internationally trained nurses in healthcare settings, as well as outlining areas for further research. The study will be the first of its type to systematically review and synthesize talent management practices for internationally trained nurses. In particular, the findings will provide the latest, validated evidence to narrate the development talent management practices specifically in relation to the strategically important cohort of internationally trained nurses in healthcare organizations. It will also help create a pipeline of suitably qualified candidates for future roles, as well as helping internationally trained nurses identify career trajectories. By systematically gathering and analyzing the relevant research, a stakeholder informed evidence-based approach to talent management for this cohort can be informed as a way of improving the quality and safety of care to the patient.

The aim of this study was to assess differences in cervical cancer screening and treatment outcomes by HIV status in a routine programmatic setting with a high generalized HIV prevalence. Women living with HIV (WLHIV) are at heightened risk of developing cervical cancer and the World Health Organization recommends all WLHIV who are sexually active be screened, regardless of age. In 2018, Namibia's Ministry of Health and Social Services introduced a screen-and-treat approach using visual inspection with acetic acid (VIA) and ablative treatment with cryotherapy or thermocoagulation with a focus on screening HIV-positive women due to Namibia's 11.5% prevalence of HIV in women aged 15-49. Using program data from October 2018 to March 2020 from seven of the country's 14 regions, we calculated descriptive statistics and chi-square tests to test the statistical significance of differences in VIA-positivity, ineligibility for ablative treatment, treatment completion, and same day treatment completion by HIV status. Between October 2018 and March 2020, the program conducted 14,786 cervical cancer screenings. Among 8,150 women who received their first VIA screening, more WLHIV screened VIA-positive (17%) than HIV-negative women (15%). This difference was statistically significant (p = 0.02). Among 2,272 women who screened VIA-positive at any screening, 1,159 (82%) completed ablative treatment. This suggests ablative treatment is feasible and acceptable in resource-limited settings. WLHIV were also more likely to complete treatment than HIV-negative women (p

Our changing climate poses growing challenges for effective management of marine life, ocean ecosystems, and human communities. Which species are most vulnerable to climate change, and where should management focus efforts to reduce these risks? To address these questions, the National Oceanic and Atmospheric Administration (NOAA) Fisheries Climate Science Strategy called for vulnerability assessments in each of NOAA's ocean regions. The Pacific Islands Vulnerability Assessment (PIVA) project assessed the susceptibility of 83 marine species to the impacts of climate change projected to 2055. In a standard Rapid Vulnerability Assessment framework, this project applied expert knowledge, literature review, and climate projection models to synthesize the best available science towards answering these questions. Here we: (1) provide a relative climate vulnerability ranking across species; (2) identify key attributes and factors that drive vulnerability; and (3) identify critical data gaps in understanding climate change impacts to marine life. The invertebrate group was ranked most vulnerable and pelagic and coastal groups not associated with coral reefs were ranked least vulnerable. Sea surface temperature, ocean acidification, and oxygen concentration were the main exposure drivers of vulnerability. Early Life History Survival and Settlement Requirements was the most data deficient of the sensitivity attributes considered in the assessment. The sensitivity of many coral reef fishes ranged between Low and Moderate, which is likely underestimated given that reef species depend on a biogenic habitat that is extremely threatened by climate change. The standard assessment methodology originally developed in the Northeast US, did not capture the additional complexity of the Pacific region, such as the diversity, varied horizontal and vertical distributions, extent of coral reef habitats, the degree of dependence on vulnerable habitat, and wide range of taxa, including data-poor species. Within these limitations, this project identified research needs to sustain marine life in a changing climate.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Background Men with a newly diagnosed prostate cancer are often treated by surgery. The time window between cancer diagnosis and surgery causes high levels of uncertainty and stress, which negatively impact quality of life (QoL). We previously reported a larger intervention pilot study which demonstrated that participation in a community-based pre-operative exercise programme significantly improved physical fitness and health-related quality of life in men with prostate cancer prior to surgery. The aim of the current pilot study was to get an insight into men’s perceptions of wellbeing and QoL following completion of the pre-operative exercise programme. Methods From November 2017 to June 2018, men scheduled for prostate cancer surgery were recruited and took part in a prescribed community-based pre-operative exercise programme in the time available between referral and surgery. Following completion of the pre-operative exercise programme (within 1 week before surgery), participants took part in one semi-structured interview which explored four broad QoL domains: physical, psychological, social, and spiritual wellbeing. Data were analysed using thematic analysis (a bottom up/inductive analysis). Results Eleven men were recruited: mean standard deviation (SD) age was 60 ± 7 years. Data supported four main themes. Participation in the community-based pre-operative exercise training programme (over a mean (SD) of 4 ± 2 weeks) provided participants with: 1) a teachable moment; 2) a journey of preparation; 3) a sense of optimism; and 4) social connectedness prior to surgery. Conclusion This study provides an insight into how the exercise programme impacted wellbeing and QoL in men preparing for prostate cancer surgery. These findings highlight the important role that exercise prehabilitation plays for men preparing for prostate cancer surgery. Such exercise programmes can be easily implemented into standard cancer pathways by establishing relationships between hospital teams and community exercise programmes.

It was recently shown that quantum annealing can be used as an effective, fast subroutine in certain types of matrix factorization algorithms. The quantum annealing algorithm performed best for quick, approximate answers, but performance rapidly plateaued. In this paper, we utilize reverse annealing instead of forward annealing in the quantum annealing subroutine for nonnegative/binary matrix factorization problems. After an initial global search with forward annealing, reverse annealing performs a series of local searches that refine existing solutions. The combination of forward and reverse annealing significantly improves performance compared to forward annealing alone for all but the shortest run times.

Introduction Monitoring clinical safety of voluntary medical male circumcision (VMMC) is critical to minimize risk as VMMC programs for HIV prevention are scaled. This cross-sectional analysis describes the adverse event (AE) profile of a large-scale, routine VMMC program and identifies factors associated with the development, severity, and timing of AEs to provide recommendations for program quality improvement. Materials and methods From 2015–2018 there were 28,990 circumcisions performed in International Training and Education Center for Health (I-TECH) supported regions of Namibia in collaboration with the Ministry of Health and Social Services. Two routine follow-up visits after VMMC were scheduled to identify clients with AEs. Summary statistics were used to describe characteristics of all VMMC clients and the subset who experienced an AE. We used chi-square tests to evaluate associations between AE timing, patient age, and other patient and AE characteristics. We used a logistic regression model to explore associations between patient characteristics and AE severity. Results Of the 498 clients with AEs (AE rate of 1.7%), 40 (8%) occurred ≤2 days, 262 (53%) occurred 3–7 days, 161 (32%) between day 8 and 14, and 35 (7%) were ≥15 days post-VMMC. Early AEs (on or before day 2) tended to be severe and categorized as bleeding, while infections were the most common AEs occurring later (pConclusions Almost 40% of AEs occurred after the second follow-up visit, of which 179 (91%) were infections. Improvements in pre-surgical and post-surgical counselling and post-operative educational materials encouraging clients to seek care at any time, adoption of alternative follow-up methods, and the addition of a third follow-up visit may improve outcomes for patients. Enhancing post-surgical counselling and emphasizing wound care for younger VMMC clients and their caregivers could help mitigate elevated risk of infection.

BackgroundFew studies have examined the best way to convey the probability of serious events occurring in the future (i.e., risk of stroke or death) to persons with low numeracy or graph literacy proficiency. To address this gap, we developed and user-tested a bar graph and compared it to icon arrays to assess its impact on understanding and preference for viewing risk information.ObjectivesTo determine the: (i) formats' impact on participants' understanding of risk information; (ii) formats' impact on understanding and format preference across numeracy and graph literacy subgroups; (iii) rationale supporting participants' preference for each graphical display format.MethodsAn online sample (evenly made up of participants with high and low objective numeracy and graph literacy) was randomized to view either the icon array or the bar graph. Each format conveyed the risk of major stroke and death five years after choosing surgery, a stent, or medication to treat carotid artery stenosis. Participants answered questions to assess their understanding of the risk information. Lastly, both formats were presented in parallel, and participants were asked to identify their preferred format to view risk information and explain their preference.ResultsOf the 407 participants, 197 were assigned the icon array and 210 the bar graph. Understanding of risk information and format preference did not differ significantly between the two trial arms, irrespective of numeracy and graph literacy proficiency. High numeracy and graph literacy proficiency was associated with high understanding (pConclusionWe found no evidence to demonstrate the superiority of one format over another on understanding. The majority of participants preferred viewing the risk information using the bar graph format.

Successful scale-up of PrEP for HIV prevention in African adolescent girls and young women (AGYW) requires integration of PrEP into young women's everyday lives. We conducted interviews and focus group discussions with 137 AGYW PrEP users aged 16-25 from South Africa and Kenya. Individual and relational enablers and disablers were explored at key moments during their PrEP-user journey from awareness, initiation and early use through persistence, including PrEP pauses, restarts, and discontinuation. PrEP uptake was facilitated when offered as part of an integrated sexual reproductive health service, but hampered by low awareness, stigma and misconceptions about PrEP in the community. Daily pill-taking was challenging for AGYW due to individual, relational and structural factors and PrEP interruptions (intended or unintended) were described as part of AGYW's PrEP-user journey. Disclosure, social support, adolescent-friendly health counseling, and convenient access to PrEP were reported as key enablers for PrEP persistence.

Using a population-based, panel survey, we study how egocentric social networks change over time, and the relationship between egocentric network properties and health and pro-social behaviors. We find that the number of prosocial activities is strongly positively associated with having more friends, or an increase in degree, with approximately 0.04 more prosocial behaviors expected for every friend added. Moreover, having more friends is associated with an improvement in health, while being healthy and prosocial is associated with closer relationships. Specifically, a unit increase in health is associated with an expected 0.45 percentage-point increase in average closeness, while adding a prosocial activity is associated with a 0.46 percentage-point increase in the closeness of one's relationships. Furthermore, a tradeoff between degree and closeness of social contacts was observed. As the number of close social contacts increases by one, the estimated average closeness of each individual contact decreases by approximately three percentage-points. The increased awareness of the importance of spillover effects in health and health care makes the ascertainment of egocentric social networks a valuable complement to investigations of the relationship between socioeconomic factors and health.

Using a population-based, panel survey, we study how egocentric social networks change over time, and the relationship between egocentric network properties and health and pro-social behaviors. We find that the number of prosocial activities is strongly positively associated with having more friends, or an increase in degree, with approximately 0.04 more prosocial behaviors expected for every friend added. Moreover, having more friends is associated with an improvement in health, while being healthy and prosocial is associated with closer relationships. Specifically, a unit increase in health is associated with an expected 0.45 percentage-point increase in average closeness, while adding a prosocial activity is associated with a 0.46 percentage-point increase in the closeness of one's relationships. Furthermore, a tradeoff between degree and closeness of social contacts was observed. As the number of close social contacts increases by one, the estimated average closeness of each individual contact decreases by approximately three percentage-points. The increased awareness of the importance of spillover effects in health and health care makes the ascertainment of egocentric social networks a valuable complement to investigations of the relationship between socioeconomic factors and health.

Alphaviruses such as Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV) are arboviruses that can cause severe zoonotic disease in humans. Both VEEV and EEEV are highly infectious when aerosolized and can be used as biological weapons. Vaccines and therapeutics are urgently needed, but efficacy determination requires animal models. The cynomolgus macaque (Macaca fascicularis) provides a relevant model of human disease, but questions remain whether vaccines or therapeutics can mitigate CNS infection or disease in this model. The documentation of alphavirus encephalitis in animals relies on traditional physiological biomarkers and behavioral/neurological observations by veterinary staff; quantitative measurements such as electroencephalography (EEG) and intracranial pressure (ICP) can recapitulate underlying encephalitic processes. We detail a telemetry implantation method suitable for continuous monitoring of both EEG and ICP in awake macaques, as well as methods for collection and analysis of such data. We sought to evaluate whether changes in EEG/ICP suggestive of CNS penetration by virus would be seen after aerosol exposure of naïve macaques to VEEV IC INH9813 or EEEV V105 strains compared to mock-infection in a cohort of twelve adult cynomolgus macaques. Data collection ran continuously from at least four days preceding aerosol exposure and up to 50 days thereafter. EEG signals were processed into frequency spectrum bands (delta: [0.4 - 4Hz); theta: [4 - 8Hz); alpha: [8-12Hz); beta: [12-30] Hz) and assessed for viral encephalitis-associated changes against robust background circadian variation while ICP data was assessed for signal fidelity, circadian variability, and for meaningful differences during encephalitis. Results indicated differences in delta, alpha, and beta band magnitude in infected macaques, disrupted circadian rhythm, and proportional increases in ICP in response to alphavirus infection. This novel enhancement of the cynomolgus macaque model offers utility for timely determination of onset, severity, and resolution of encephalitic disease and for the evaluation of vaccine and therapeutic candidates.

Increasing urbanisation has led to a greater use of artificial structures by bats as alternative roost sites. Despite the widespread presence of bats, roost availability may restrict their distribution and abundance in urban environments. There is limited quantitative information on the drivers of bat roost selection and roosting preferences, particularly in African bats. We explore the factors influencing roost selection in the Mauritian tomb bat (Taphozous mauritianus), within an urban landscape in Lilongwe city, Malawi. Eight building and five landscape features of roosts were compared with both adjacent and random control buildings throughout the city. Bat occupied buildings were situated closer to woodland (mean 709m) compared to random buildings (mean 1847m) but did not differ in any other landscape features explored. Roosts were situated on buildings with larger areas and taller walls, suggesting bats select features for predator-avoidance and acoustic perception when leaving the roost. Bats preferred buildings with exposed roof beams which may provide refuge from disturbance. Whilst roosts are situated more often on brick walls, this feature was also associated with landscape features, therefore its importance in roost selection is less clear. These results are indicative that T. mauritianus selects roosts at both the building and landscape level. The selectivity of T. mauritianus in relation to its roost sites implies that preferred roosts are a limited resource, and as such, conservation actions should focus on protecting roost sites and the woodland bats rely on.

ObjectivesGraphic display formats are often used to enhance health information. Yet limited attention has been paid to graph literacy in people of lower education and lower socioeconomic status (SES). This study aimed to: 1) examine the relationship between graph literacy, numeracy, health literacy and sociodemographic characteristics in a Medicaid-eligible population 2) determine the impact of graph literacy on comprehension and preference for different visual formats.MethodsWe conducted a cross-sectional online survey among people in the US on Medicaid, and of presumed lower education and SES.ResultsThe mean graph literacy score among 436 participants was 1.47 (SD 1.05, range: 0 to 4). Only graph literacy was significantly associated with overall comprehension (p < .001). Mean comprehension scores were highest for the table format (1.91), closely followed by bar graph (1.85) and icon array (1.80). Information comprehension was aligned with preference scores.ConclusionsGraph literacy in a Medicaid-eligible population was lower than previous estimates in the US. Tables were better understood, with icon arrays yielding the lowest score. Preferences aligned with comprehension.Practice implicationsIt may be necessary to reconsider the use of graphic display formats when designing information for people with lower educational levels. Further research is needed.

Introduction: Clinical trials evaluating the effectiveness of falls prevention interventions for people with Multiple Sclerosis (MS), Parkinson's Disease (PD) and stroke measure heterogeneous outcomes, often omitting those meaningful to patients. A core outcome set (COS) is a standardised set of outcomes that should be assessed in all trials within a research area. The aim of this study was to develop a COS for evaluating mixed-diagnosis falls prevention interventions for people with MS, PD and stroke in non-acute and community settings, with input from relevant stakeholder groups. Methods: Previously published research undertaken by the team, including a qualitative study with 20 patients and a review of the literature, were used to derive a longlist of potential outcomes. Outcomes were prioritised for inclusion in the COS using a three-round online Delphi survey. A multi-stakeholder, consensus meeting was conducted to agree upon the final COS and to provide a recommendation for a single outcome measure for each outcome in the COS. Results: Forty-eight participants were recruited across four stakeholder groups (researchers, patients, clinicians, and service-planners/policymakers). A total of 42 participants (87.5%) completed all three rounds of the surveys. Sixty-two outcomes were considered for inclusion in the COS throughout the Delphi process. A total of 15 participants attended the consensus meeting where they agreed upon the final COS and accompanying measurement instruments: fall incidence, injurious fall incidence, quality of life, falls self-efficacy, fear of falling, activity curtailment due to fear of falling, and cost-effectiveness. Attendees at the consensus meeting recommended that the proposed mechanism of impact of an intervention is considered when selecting additional outcomes outside of those in the COS to assess. Conclusions: This study identified a COS for evaluating the effectiveness of mixed-diagnosis falls prevention interventions for people with MS, PD and stroke. It is recommended that this COS and accompanying measurement instruments be used in all future trials in this research area so that findings can be combined and compared. [ABSTRACT FROM AUTHOR]

A healthy gastrointestinal (GI) tract with a properly established microbiota is necessary for a foal to develop into a healthy weanling. A foal's health can be critically impacted by aberrations in the microbiome such as with diarrhea which can cause great morbidity and mortality in foals. In this study, we hypothesized that gut establishment in the foal transitioning from a diet of milk to a diet of grain, forage, and pasture would be detectable through analyses of the fecal microbiotas. Fecal samples from 37 sets of foals and mares were collected at multiple time points ranging from birth to weaning. Bacterial DNA was isolated from the samples, and the V4 domain of bacterial 16S rRNA genes were amplified via polymerase chain reaction. Next generation sequencing was then performed on the resulting amplicons, and analyses were performed to characterize the microbiome as well as the relative abundance of microbiota present. We found that bacterial population compositions followed a pattern throughout the early life of the foal in an age-dependent manner. As foals transitioned from milk consumption to a forage and grain diet, there were recognizable changes in fecal microbial compositions from initial populations predominant in the ability to metabolize milk to populations capable of utilizing fibrous plant material. We were also able to recognize differences in microbial populations amongst diarrheic foals as well as microbial population differences associated with differences in management styles between facilities. Future efforts will gauge the effects of lesser abundant bacterial populations that could also be essential to GI health, as well as to determine how associations between microbial population profiles and animal management practices can be used to inform strategies for improving upon the health and growth of horses overall.

Pseudomonas syringae is a taxon of plant pathogenic bacteria that can colonize and proliferate within the interior space of leaf tissue. This process requires P. syringae to rapidly upregulate the production of virulence factors including a type III secretion system (T3SS) that suppress host defenses. GacS/A is a two-component system that regulates virulence of many plant and animal pathogenic bacteria including P. syringae. We recently investigated the virulence defect of strain AC811, a Tn5::gacA mutant of P. syringae pv. tomato DC3000 that is less virulent on Arabidopsis. We discovered that decreased virulence of AC811 is not caused by loss of GacA function. Here, we report the molecular basis of the virulence defect of AC811. We show that AC811 possesses a nonsense mutation in anmK, a gene predicted to encode a 1,6-anhydromuramic acid kinase involved in cell wall recycling. Expression of a wild-type allele of anmK partially increased growth of AC811 in Arabidopsis leaves. In addition to the defective anmK allele, we also show that the Tn5 insertion in gacA exerts a polar effect on uvrC, a downstream gene encoding a regulator of DNA damage repair. Expression of the wild-type anmK allele together with increased expression of uvrC fully restored the virulence of AC811 during infection of Arabidopsis. These results demonstrate that defects in anmK and uvrC are together sufficient to account for the decreased virulence of AC811, and suggest caution is warranted in assigning phenotypes to GacA function based on insertional mutagenesis of the gacA-uvrC locus.

D-Wave quantum annealers represent a novel computational architecture and have attracted significant interest. Much of this interest has focused on the quantum behavior of D-Wave machines, and there have been few practical algorithms that use the D-Wave. Machine learning has been identified as an area where quantum annealing may be useful. Here, we show that the D-Wave 2X can be effectively used as part of an unsupervised machine learning method. This method takes a matrix as input and produces two low-rank matrices as output-one containing latent features in the data and another matrix describing how the features can be combined to approximately reproduce the input matrix. Despite the limited number of bits in the D-Wave hardware, this method is capable of handling a large input matrix. The D-Wave only limits the rank of the two output matrices. We apply this method to learn the features from a set of facial images and compare the performance of the D-Wave to two classical tools. This method is able to learn facial features and accurately reproduce the set of facial images. The performance of the D-Wave shows some promise, but has some limitations. It outperforms the two classical codes in a benchmark when only a short amount of computational time is allowed (200-20,000 microseconds), but these results suggest heuristics that would likely outperform the D-Wave in this benchmark.

IntroductionMany e-cigarette users find the variety of e-cigarette flavors appealing. We examined whether preferences for e-liquid flavors and the total number of flavors preferred differed between samples of adolescent and adult e-cigarette users. We also examined whether these preferences were associated with e-cigarette use frequency for adolescents or adults, respectively.Materials and methodsThe analytic samples comprised 1) 396 adolescent, past-month e-cigarette users from 5 Connecticut high schools who completed an anonymous, school-based survey in Fall 2014 (56.1% male; 16.18 [1.18] years; 42.2% past-month smokers), and 2) 590 adult, past-month e-cigarette users who completed an anonymous, MTurk survey in Fall 2014 (53.7% male; 34.25 [9.89] years; 51.2% past-month smokers).ResultsCompared to adults, a larger proportion of adolescents preferred fruit, alcohol, and "other"-flavored e-liquids, whereas adults disproportionately preferred tobacco, menthol, mint, coffee, and spice-flavored e-liquids (p-values < .05). Adults also preferred a greater total number of flavors compared to adolescents and used e-cigarettes more frequently (p-values < .001). Flavor preferences uniquely were associated with frequency of e-cigarette use within the adolescent sample; the total number of flavors preferred was associated with more days of e-cigarette use (ηp2 = 0.04), as were preferences for fruit (ηp2 = 0.02), dessert (ηp2 = 0.02), and alcohol-flavored (ηp2 = 0.02) e-liquids.ConclusionsFlavor preferences differed between adolescent and adult samples. While youth reported less frequent e-cigarette use overall, their preferences for specific flavors and the total number of flavors preferred were associated with more days of e-cigarette use, indicating that flavor preferences may play an important role in adolescent e-cigarette use.

Circadian rhythmicity, the 24-hour cycle responsive to light and dark, is determined by periodic oscillations in gene transcription. This phenomenon has broad ramifications in physiologic function. Recent work has disclosed more cycles in gene transcription, and to the uncovering of these we apply a novel signal processing methodology known as the pencil method and compare it to conventional parametric, nonparametric, and statistical methods. METHODS:In order to assess periodicity of gene expression over time, we analyzed a database derived from livers of mice entrained to a 12-hour light/12-hour dark cycle. We also analyzed artificially generated signals to identify differences between the pencil decomposition and other alternative methods. RESULTS:The pencil decomposition revealed hitherto-unsuspected oscillations in gene transcription with 12-hour periodicity. The pencil method was robust in detecting the 24-hour circadian cycle that was known to exist, as well as confirming the existence of shorter-period oscillations. A key consequence of this approach is that orthogonality of the different oscillatory components can be demonstrated. thus indicating a biological independence of these oscillations, that has been subsequently confirmed empirically by knocking out the gene responsible for the 24-hour clock. CONCLUSION:System identification techniques can be applied to biological systems and can uncover important characteristics that may elude visual inspection of the data. SIGNIFICANCE:The pencil method provides new insights on the essence of gene expression and discloses a wide variety of oscillations in addition to the well-studied circadian pattern. This insight opens the door to the study of novel mechanisms by which oscillatory gene expression signals exert their regulatory effect on cells to influence human diseases.

Tularemia, also known as rabbit fever, is a severe zoonotic disease in humans caused by the gram-negative bacterium Francisella tularensis (Ft). While there have been a number of attempts to develop a vaccine for Ft, few candidates have advanced beyond experiments in inbred mice. We report here that a prime-boost strategy with aerosol delivery of recombinant live attenuated candidate Ft S4ΔaroD offers significant protection (83% survival) in an outbred animal model, New Zealand White rabbits, against aerosol challenge with 248 cfu (11 LD50) of virulent type A Ft SCHU S4. Surviving rabbits given two doses of the attenuated strains by aerosol did not exhibit substantial post-challenge fevers, changes in erythrocyte sedimentation rate or in complete blood counts. At a higher challenge dose (3,186 cfu; 139 LD50), protection was still good with 66% of S4ΔaroD-vaccinated rabbits surviving while 50% of S4ΔguaBA vaccinated rabbits also survived challenge. Pre-challenge plasma IgG titers against Ft SCHU S4 corresponded with survival time after challenge. Western blot analysis found that plasma antibody shifted from predominantly targeting Ft O-antigen after the prime vaccination to other antigens after the boost. These results demonstrate the superior protection conferred by a live attenuated derivative of virulent F. tularensis, particularly when given in an aerosol prime-boost regimen.

[This corrects the article DOI: 10.1371/journal.pone.0189015.].

The appeal of sweet electronic cigarette flavors makes it important to identify the chemical compounds that contribute to their sweetness. While volatile chemicals that produce sweet aromas have been identified in e-liquids, there are no published reports of sugars or artificial sweeteners in commercial e-liquids. However, the sweetener sucralose is marketed as an e-liquid additive to commercial flavors. The primary aims of the study were to determine if sucralose is delivered in sufficient concentration in the inhaled aerosol to enhance flavor sweetness, and whether the amount delivered depends on the e-liquid delivery system. Thirty-two adult smokers rated flavor intensity, sweetness, harshness and liking/disliking for 4 commercial flavors with and without sucralose (1%) using 2 e-cigarette delivery systems (cartridge and tank). Participants alternately vaped normally or with the nose pinched closed to block perception of volatile flavor components via olfaction. LC/MS was used to measure the concentration of sucralose in the e-liquid aerosols using a device that mimicked vaping. Sweetness and flavor intensity were perceived much more strongly when olfaction was permitted. The contribution of sucralose to sweetness was significant only for the cartridge system, and the chemical analysis showed that the concentration of sucralose in the aerosol was higher when the cartridge was used. Together these findings indicate that future regulation of sweet flavor additives should focus first on the volatile constituents of e-liquids with the recognition that artificial sweeteners may also contribute to flavor sweetness depending upon e-cigarette design.

Although several studies have documented challenges related to inadequate adherence to antiretroviral therapy (ART) and high loss to follow-up (LTFU) among Option B+ women, there is limited understanding of why these challenges occur and how to address them. This qualitative study examines women's experiences with ART adherence and retention in care. Between July and October 2015, in-depth interviews were conducted with 39 pregnant and lactating women who initiated ART at Bwaila Hospital in Lilongwe, Malawi. Study participants included 14 in care and 25 out of care women, according to facility records. Data were analyzed using an inductive, open-coding approach to thematic analysis. Ten of the respondents (7 out of care, 3 in-care) had stopped and re-started treatment before the interview date. One of the most important factors influencing adherence and retention was the strength of women's support systems. In contrast to women in-care, most out-of-care women lacked emotional and financial support from male partners, received minimal counseling from providers at initiation, lacked designated guardians to assist with medication refills or clinic appointments, and were highly mobile. Mobility led to difficulties in accessing treatment in new settings. The most common reasons women re-started treatment following interruptions were due to providers' counseling and encouragement and the mother's desire to be healthy. Improved counseling at initiation, active follow-up counseling, women's economic empowerment interventions, promotion of peer counseling schemes and meaningful engagement of male partners can help in addressing the identified barriers and promoting sustained retention of Option B+ women.

BACKGROUND:Tuberculosis (TB) is difficult to diagnose in children using molecular tests, because children have difficulty providing respiratory samples. Stool could replace sputum for diagnostic TB testing if adequate sample processing techniques were available. METHODS:We developed a rapid method to process large volumes of stool for downstream testing by the Xpert MTB/RIF (Xpert) TB-detection assay. The method was tested and optimized on stool samples spiked with known numbers of M. tuberculosis colony forming units (CFU), and stools from M. tuberculosis-infected cynomolgus macaques (Macaca fascicularis). Performance was scored on number of positive Xpert tests, the cycle thresholds (Cts) of the Xpert sample-processing control (SPC), and the Cts of the M. tuberculosis-specific rpoB probes. The method was then validated on 20 confirmed TB cases and 20 controls in Durban, South Africa. RESULTS:The assay's analytical limit of detection was 1,000 CFU/g of stool. As much as one gram of spiked stool could be tested without showing increased PCR inhibition. In analytical spiking experiments using human stool, 1g samples provided the best sensitivity compared to smaller amounts of sample. However, in Macaques with TB, 0.6g stool samples performed better than either 0.2g or 1.2g samples. Testing the stool of pediatric TB suspects and controls suggested an assay sensitivity of 85% (95% CI 0.6-0.9) and 84% (95% CI 0.6-0.96) for 0.6g and 1.2g stool samples, respectively, and a specificity of 100% (95% CI 0.77-1) and 94% (95% CI 0.7-0.99), respectively. CONCLUSION:This novel approach may permit simple and rapid detection of TB using pediatric stool samples.

A conventional study design among medical and biological experimentalists involves collecting multiple measurements from a study subject. For example, experiments utilizing mouse models in neuroscience often involve collecting multiple neuron measurements per mouse to increase the number of observations without requiring a large number of mice. This leads to a form of statistical dependence referred to as clustering. Inappropriate analyses of clustered data have resulted in several recent critiques of neuroscience research that suggest the bar for statistical analyses within the field is set too low. We compare naïve analytical approaches to marginal, fixed-effect, and mixed-effect models and provide guidelines for when each of these models is most appropriate based on study design. We demonstrate the influence of clustering on a between-mouse treatment effect, a within-mouse treatment effect, and an interaction effect between the two. Our analyses demonstrate that these statistical approaches can give substantially different results, primarily when the analyses include a between-mouse treatment effect. In a novel analysis from a neuroscience perspective, we also refine the mixed-effect approach through the inclusion of an aggregate mouse-level counterpart to a within-mouse (neuron level) treatment as an additional predictor by adapting an advanced modeling technique that has been used in social science research and show that this yields more informative results. Based on these findings, we emphasize the importance of appropriate analyses of clustered data, and we aim for this work to serve as a resource for when one is deciding which approach will work best for a given study.

Although numerous studies provide evidence that active patient engagement with health care providers improves critical outcomes such as medication adherence, very few of these have been done in low resource settings. In Namibia, patient education and empowerment trainings were conducted in four antiretroviral (ART) clinics to increase patient engagement during patient-provider interactions. This qualitative study supplements findings from a randomized controlled trial, by analyzing data from 10 in-depth patient interviews and 94 training evaluation forms. A blended approach of deductive and inductive coding was used to understand training impact. Findings indicated the trainings increased patients' self-efficacy through a combination of improved HIV-related knowledge, greater communication skills and enhanced ability to overcome complex psychosocial barriers, such as fear of speaking up to providers. This study suggests patient empowerment training may be a powerful method to engage HIV patients in their own care and treatment.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Amyloid-reactive IgGs isolated from pooled blood of normal individuals (pAbs) have demonstrated clinical utility for amyloid diseases by in vivo targeting and clearing amyloidogenic proteins and peptides. We now report the following three novel findings on pAb conformer's binding to amyloidogenic aggregates: 1) pAb aggregates have greater activity than monomers (HMW species > dimers > monomers), 2) pAbs interactions with amyloidogenic aggregates at least partially involves unconventional (non-CDR) interactions of F(ab) regions, and 3) pAb's activity can be easily modulated by trace aggregates generated during sample processing. Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg), had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of Aβ- and Cibacron blue-isolated IVIg IgGs. Human pAb conformer's binding to amyloidogenic aggregates was retained in normal human sera, and mimicked by murine pAbs isolated from normal pooled plasmas. An unconventional (non-CDR) component to pAb's activity was indicated from control human mAbs, generated against non-amyloid targets, binding to aggregated Aβ and TTR. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Taken together, our findings strongly support further investigations on the physiological function and clinical utility of the inherent anti-amyloid activities of monomeric but not aggregated IgGs.

Triple negative breast cancer (TNBC) has the poorest prognosis of all types of breast cancer and currently lacks efficient targeted therapy. Chemotherapy is the traditional standard-of-care for TNBC, but is frequently accompanied by severe side effects. Despite the fact that high expression of steroid receptor coactivator 3 (SRC-3) is correlated with poor survival in estrogen receptor positive breast cancer patients, its role in TNBC has not been extensively investigated. Here, we show that high expression of SRC-3 correlates with both poor overall survival and post progression survival in TNBC patients, suggesting that SRC-3 can serve as a prognostic marker for TNBC. Furthermore, we demonstrated that bufalin, a SRC-3 small molecule inhibitor, when introduced even at nM concentrations, can significantly reduce TNBC cell viability and motility. However, because bufalin has minimal water solubility, its in vivo application is limited. Therefore, we developed a water soluble prodrug, 3-phospho-bufalin, to facilitate its in vivo administration. In addition, we demonstrated that 3-phospho-bufalin can effectively inhibit tumor growth in an orthotopic TNBC mouse model, suggesting its potential application as a targeted therapy for TNBC treatment.