Diverse Sources and Latent Reservoirs of Community-Associated Clostridioides difficile Infection.

Clostridioides difficile (C. difficile) is a spore-forming, toxin-producing, anaerobic bacterium infecting the human gastrointestinal tract, causing diarrhea and life-threatening colitis. C. difficile epidemiology continues to evolve, and it is recognized as a major community-associated pathogen in addition to its established role in causing healthcare-associated infection. While current surveillance and prevention measures mainly focus on healthcare-associated C. difficile infections, much less is known about the factors driving community-associated C. difficile infections. This review highlights the potential contribution of reservoirs, including asymptomatic carriers, to community-associated C. difficile transmission. The reservoirs discussed in this review provide potential avenues for research to better understand and reduce community-associated transmission of C. difficile.

Crisis Communication and Public Perception of COVID-19 Risk in the Era of Social Media.

A number of important principles in effective risk communication established in the late 20th century can provide important scientific insight into patient response to the risks posed by coronavirus disease 2019 (COVID-19). Early risk communication scholars found acceptability of risk was shaped by 2 key components: hazard and outrage. The number of people who are exposed, infected, and fall ill can be considered the hazard. How the public and patients and respond to messages regarding risk mitigation relates to outrage. Social and cultural factors, immediacy, uncertainty, familiarity, personal control, scientific uncertainty, and trust in institutions and media all shape perception and response to risk mesaging. Outrage factors influence the ever-changing public understanding of COVID-19 risk. In concert, hazard and outrage along with cultural and economic context shape adherence to, and overall acceptance of, personal mitigation strategies including wearing facemasks and social distancing among the general public. The spread of misinformation on social media also provides both challenges and opportunities for clinicians. Social media offers an opportunity for experts to quickly convey true information about hazards, but offers others the opportunity to counter this with the spread of misinformation and exacerbate outrage. We propose strategies for infectious diseases clinicians to apply risk communication principles and frameworks to improve patient care and public message development in response to COVID-19.

West Nile virus methyltransferase domain interacts with protein kinase G.

BACKGROUND: The flaviviral nonstructural protein 5 (NS5) is a phosphoprotein, though the precise identities and roles of many specific phosphorylations remain unknown. Protein kinase G (PKG), a cGMP-dependent protein kinase, has previously been shown to phosphorylate dengue virus NS5. METHODS: We used mass spectrometry to specifically identify NS5 phosphosites. Co-immunoprecipitation assays were used to study protein-protein interactions. Effects on viral replication were measured via replicon system and plaque assay titering. RESULTS: We identified multiple sites in West Nile virus (WNV) NS5 that are phosphorylated during a WNV infection, and showed that the N-terminal methyltransferase domain of WNV NS5 can be specifically phosphorylated by PKG in vitro. Expressing PKG in cell culture led to an enhancement of WNV viral production. We hypothesized this effect on replication could be caused by factors beyond the specific phosphorylations of NS5. Here we show for the first time that PKG is also able to stably interact with a viral substrate, WNV NS5, in cell culture and in vitro. While the mosquito-borne WNV NS5 interacted with PKG, tick-borne Langat virus NS5 did not. The methyltransferase domain of NS5 is able to mediate the interaction between NS5 and PKG, and mutating positive residues in the αE region of the methyltransferase interrupts the interaction. These same mutations completely inhibited WNV replication. CONCLUSIONS: PKG is not required for WNV replication, but does make a stable interaction with NS5. While the consequence of the NS5:PKG interaction when it occurs is unclear, mutational data demonstrates that this interaction occurs in a region of NS5 that is otherwise necessary for replication. Overall, the results identify an interaction between virus and a cellular kinase and suggest a role for a host kinase in enhancing flaviviral replication.

Phosphorylation events during viral infections provide potential therapeutic targets.

For many medically relevant viruses, there is now considerable evidence that both viral and cellular kinases play important roles in viral infection. Ultimately, these kinases, and the cellular signaling pathways that they exploit, may serve as therapeutic targets for treating patients. Currently, small molecule inhibitors of kinases are under investigation as therapy for herpes viral infections. Additionally, a number of cellular or host-directed tyrosine kinase inhibitors that have been previously FDA approved for cancer treatment are under study in animal models and clinical trials, as they have shown promise for the treatment of various viral infections as well. This review will highlight the wide range of viral proteins phosphorylated by viral and cellular kinases, and the potential for variability of kinase recognition sites within viral substrates to impact phosphorylation and kinase prediction. Research studying kinase-targeting prophylactic and therapeutic treatments for a number of viral infections will also be discussed.

Integrating infection control and environmental management work systems to prevent Clostridioides difficile infection.

Effective infection prevention and control within health care settings requires collaboration and coordination between infection control and environmental management teams. However, the work systems of these teams can be difficult to integrate despite their shared goals. We provide results from a qualitative study of Clostridioides difficile infection prevention in Veterans Affairs facilities regarding challenges in coordination between these teams and opportunities to improve coordination and maximize infection prevention activities.

Supporting Midcareer Women Faculty in Academic Medicine Through Mentorship and Sponsorship.

ABSTRACT: Midcareer women faculty face unique career challenges that may benefit from mentorship and sponsorship, yet such programs focused on the needs of this career phase are scarce in academic medicine. Many midcareer faculty require intentional and individual career planning to choose a path from the broad array of options in academic medicine. Ambiguous promotion criteria, increased workloads because of service or citizenship tasks, and a lack of sponsorship are among the barriers that inhibit midcareer faculty's growth into the high-visibility roles needed for career advancement. In addition, issues faced by women midcareer faculty members may be further exacerbated by barriers such as biases, a disproportionate share of family responsibilities, and inequities in recognition and sponsorship. These barriers contribute to slower career growth and higher attrition among women midcareer faculty and ultimately an underrepresentation of women among senior leadership in academic medicine. Here, we describe how a mentoring program involving individuals (eg, mentors, mentees, and sponsors) and departments/institutions (eg, deans and career development offices) can be used to support midcareer faculty. We also provide recommendations for building a mentoring program with complementary support from sponsors targeted toward the specific needs of women midcareer faculty. A robust midcareer mentoring program can support the career growth and engagement of individual faculty members and as a result improve the diversity of academic medicine's highest ranks.

Physical distancing for care delivery in health care settings: Considerations and consequences.

As health care systems explore new ways of delivering care for patients with and without COVID-19, they must consider how to maintain physical distancing among health care workers and patients. Physical distancing in high complexity systems such as health care is particularly challenging and may benefit from a human factors and systems engineering perspective. We discuss challenges to implementing and maintaining physical distancing in health care settings and present possible solutions from a human factors and systems engineering perspective.

Gaining momentum in colorectal surgical site infection reduction through a human factors engineering approach.

Surgical site infection (SSI) prevention requires multiple interventions packaged into "bundles." The implementation of all bundle elements is key to the bundle's efficacy. A human-factors engineering approach can be used to identify key barriers and facilitators to implementing elements and develop recommendations for bundle implementation within the clinical work system.

Barriers and facilitators to influenza-like illness absenteeism among healthcare workers in a tertiary-care healthcare system, 2017-2018 influenza season.

OBJECTIVE: Influenza can be introduced and propagated in healthcare settings by healthcare workers (HCWs) working while ill with influenza. However, reasons driving this behavior are unclear. In this study, we examined barriers to and facilitators of absenteeism during the influenza season. DESIGN: Cross-sectional mixed methods study. SETTING: Ambulatory and inpatient settings in a large, tertiary-care healthcare system. METHODS: An anonymous electronic survey was sent to HCWs between June 11 and July 13, 2018, asking participants to self-report influenza-like illness (ie, ILI symptoms of fever, chills, cough, or sore throat) during the 2017-2018 influenza season. We conducted a logistical regression analysis to identify factors associated with absenteeism. RESULTS: Of 14,250 HCWs, 17% responded to the survey. Although 1,180 respondents (51%) reported symptoms of ILI, 575 (43%) did not stay home while ill. The most commonly perceived barriers to ILI absenteeism included being understaffed (odds ratio [OR], 1.78; P = .04), unable to find a replacement for work (OR, 2.26; P = .03), desiring not to use time off (OR, 2.25; P = .003), and paid by the hour or unable to afford being absent (OR, 2.05; P = .02). Common perceived facilitators of absenteeism included support from coworkers and management, clearer policy, better sick days availability, and lower perceived threat of disciplinary action. CONCLUSIONS: Reporting to work with ILI symptoms is common among HCWs. Most barriers and facilitators are related to systems. Addressing system factors, such as policies regarding sick days and sick leave and ensuring adequate backup staffing, is likely to facilitate absenteeism among ill HCWs.

Correlation of prevention practices with rates of health care-associated Clostridioides difficile infection.

OBJECTIVE: We examined Clostridioides difficile infection (CDI) prevention practices and their relationship with hospital-onset healthcare facility-associated CDI rates (CDI rates) in Veterans Affairs (VA) acute-care facilities. DESIGN: Cross-sectional study. METHODS: From January 2017 to February 2017, we conducted an electronic survey of CDI prevention practices and hospital characteristics in the VA. We linked survey data with CDI rate data for the period January 2015 to December 2016. We stratified facilities according to whether their overall CDI rate per 10,000 bed days of care was above or below the national VA mean CDI rate. We examined whether specific CDI prevention practices were associated with an increased risk of a CDI rate above the national VA mean CDI rate. RESULTS: All 126 facilities responded (100% response rate). Since implementing CDI prevention practices in July 2012, 60 of 123 facilities (49%) reported a decrease in CDI rates; 22 of 123 facilities (18%) reported an increase, and 41 of 123 (33%) reported no change. Facilities reporting an increase in the CDI rate (vs those reporting a decrease) after implementing prevention practices were 2.54 times more likely to have CDI rates that were above the national mean CDI rate. Whether a facility's CDI rates were above or below the national mean CDI rate was not associated with self-reported cleaning practices, duration of contact precautions, availability of private rooms, or certification of infection preventionists in infection prevention. CONCLUSIONS: We found considerable variation in CDI rates. We were unable to identify which particular CDI prevention practices (i.e., bundle components) were associated with lower CDI rates.

Engaging patients in health care epidemiology research: A case example.

BACKGROUND: We describe stakeholder engagement from a Patient-Centered Outcomes Research Institute-funded project to identify patients' research priorities for health care-associated infections (HAI). We summarize insights from these activities to highlight feasibility and benefits of stakeholder engagement in health care epidemiology research.Patients and caregivers who had an HAI experience were involved in a patient and caregiver stakeholder group. We engaged clinicians, infection prevention experts, state public health professionals, and quality improvement experts in an institutional stakeholder (IS) group in an academic tertiary care medical center. METHODS: Through individual and combined group activities, we identified stakeholders' HAI research priorities. Existing engagement resources from the Wisconsin Network for Research Support (WINRS) guided the process. RESULTS: Given the patients' and caregivers' experiences with HAIs, their perspectives broadened IS understanding of the impact of HAIs and the relevance of proposed research topics. After introductory activities described here, the patient and caregiver stakeholder group actively engaged with researchers and the IS group in discussing complex systems-level topics to reduce HAIs. We have sustained this engagement through continued collaboration. CONCLUSIONS: Our engagement experience provides one example of how patients can be engaged in health care epidemiology research. Our experiences and lessons learned may be helpful to others interested in stakeholder engagement.

Characterising the gut microbiome in veterans with Gulf War Illness: a protocol for a longitudinal, prospective cohort study.

INTRODUCTION: Approximately 25%-35% of the 1991 Gulf War Veteran population report symptoms consistent with Gulf War Illness (GWI), a chronic, multi-symptom illness characterised by fatigue, pain, irritable bowel syndrome and problems with cognitive function. GWI is a disabling problem for Gulf War Veterans, and there remains a critical need to identify innovative, novel therapies.Gut microbiota perturbation plays a key role in the symptomatology of other chronic multi-symptom illnesses, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Given similarities between ME/CFS and GWI and the presence of gastrointestinal disorders in GWI patients, Veterans with GWI may also have gut abnormalities like those seen with ME/CFS. In this longitudinal cohort study, we are comparing the diversity (structure) and the metagenomes (function) of the gut microbiome between Gulf War Veterans with and without GWI. If we find differences in Veterans with GWI, the microbiome could be a target for therapeutic intervention to alleviate GWI symptoms. METHODS AND ANALYSIS: Participants answer questions about diet, exercise and lifestyle factors. Participants also complete a questionnaire (based on the Kansas case definition of GWI) regarding their medical history and symptoms; we use this questionnaire to group participants into GWI versus healthy control cohorts. We plan to enrol 52 deployed Gulf War Veterans: 26 with GWI and 26 healthy controls. Participants provide stool and saliva samples weekly for an 8-week period for microbiome analyses. Participants also provide blood samples at the beginning and end of this period, which we will use to compare measures of inflammation markers between the groups. ETHICS AND DISSEMINATION: The protocol was approved by the University of Wisconsin-Madison Health Sciences Institutional Review Board and the William S. Middleton Memorial Veterans Hospital Research and Development Committee. Results of this study will be submitted for publication in a peer-reviewed journal.

Mosquito protein kinase G phosphorylates flavivirus NS5 and alters flight behavior in Aedes aegypti and Anopheles gambiae.

Many arboviral proteins are phosphorylated in infected mammalian cells, but it is unknown if the same phosphorylation events occur when insects are similarly infected. One of the mammalian kinases responsible for phosphorylation, protein kinase G (PKG), has been implicated in the behavior of multiple nonvector insects, but is unstudied in mosquitoes. PKG from Aedes aegypti was cloned, and phosphorylation of specific viral sites was monitored by mass spectrometry from biochemical and cell culture experiments. PKG from Aedes mosquitoes is able to phosphorylate dengue nonstructural protein 5 (NS5) at specific sites in cell culture and cell-free systems and autophosphorylates its own regulatory domain in a cell-free system. Injecting Aedes aegypti and Anopheles gambiae mosquitoes with a pharmacological PKG activator resulted in increased Aedes wing activity during periods of their natural diurnal/crepuscular activity and increased Anopheles nocturnal locomotor/flight activity. Thus, perturbation of the PKG signaling pathway in mosquitoes alters flight behavior. The demonstrated effect of PKG alterations is consistent with a viral PKG substrate triggering increased PKG activity. This increased PKG activity could be the mechanism by which dengue virus increases flight behavior and possibly facilitates transmission. Whether or not PKG is part of the mechanism by which dengue increases flight behavior, this report is the first to show PKG can modulate behavior in hematophagous disease vectors.

A thiopurine drug inhibits West Nile virus production in cell culture, but not in mice.

Many viruses within the Flavivirus genus cause significant disease in humans; however, effective antivirals against these viruses are not currently available. We have previously shown that a thiopurine drug, 6-methylmercaptopurine riboside (6MMPr), inhibits replication of distantly related viruses within the Flaviviridae family in cell culture, including bovine viral diarrhea virus and hepatitis C virus replicon. Here we further examined the potential antiviral effect of 6MMPr on several diverse flaviviruses. In cell culture, 6MMPr inhibited virus production of yellow fever virus, dengue virus-2 (DENV-2) and West Nile virus (WNV) in a dose-dependent manner, and DENV-2 was significantly more sensitive to 6MMPr treatment than WNV. We then explored the use of 6MMPr as an antiviral against WNV in an immunocompetent mouse model. Once a day treatment of mice with 0.5 mg 6MMPr was just below the toxic dose in our mouse model, and this dose was used in subsequent studies. Mice were treated with 6MMPr immediately after subcutaneous inoculation with WNV for eight consecutive days. Treatment with 6MMPr exacerbated weight loss in WNV-inoculated mice and did not significantly affect mortality. We hypothesized that 6MMPr has low bioavailability in the central nervous system (CNS) and examined the effect of pre-treatment with 6MMPr on viral loads in the periphery and CNS. Pre-treatment with 6MMPr had no significant effect on viremia or viral titers in the periphery, but resulted in significantly higher viral loads in the brain, suggesting that the effect of 6MMPr is tissue-dependent. In conclusion, despite being a potent inhibitor of flaviviruses in cell culture, 6MMPr was not effective against West Nile disease in mice; however, further studies are warranted to reduce the toxicity and/or improve the bioavailability of this potential antiviral drug.