NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING.

Stimulator of interferon genes (STING, also named MITA, MYPS, or ERIS) is an intracellular DNA sensor that induces type I interferon through its interaction with TANK-binding kinase 1 (TBK1). Here we found that the nucleotide-binding, leucine-rich-repeat-containing protein, NLRC3, reduced STING-dependent innate immune activation in response to cytosolic DNA, cyclic di-GMP (c-di-GMP), and DNA viruses. NLRC3 associated with both STING and TBK1 and impeded STING-TBK1 interaction and downstream type I interferon production. By using purified recombinant proteins, we found NLRC3 to interact directly with STING. Furthermore, NLRC3 prevented proper trafficking of STING to perinuclear and punctated region, known to be important for its activation. In animals, herpes simplex virus 1 (HSV-1)-infected Nlrc3(-/-) mice exhibited enhanced innate immunity and reduced morbidity and viral load. This demonstrates the intersection of two key pathways of innate immune regulation, NLR and STING, to fine tune host response to intracellular DNA, DNA virus, and c-di-GMP.

Years of life lost associated with COVID-19 deaths in the USA during the first 2 years of the pandemic.

BACKGROUND: Prior estimates of the years of life lost (YLLs) in the USA associated with coronavirus disease 2019 (COVID-19) were 1.2 million through 11 July 2020 and 3.9 million through 31 January 2021 (which roughly coincides with the first full year of the pandemic). The aim of this study is to update YLL estimates through the first 2 years of the pandemic. METHODS: We employed data regarding COVID-19 deaths through 5 February 2022 by jurisdiction, gender and age group. We used actuarial life expectancy tables by gender and age to estimate YLLs. RESULTS: We estimated roughly 9.7 million YLLs due to COVID-19 deaths. The number of YLLs per 10 000 capita was 297.5, with the highest rate in Mississippi (482.7) and the lowest in Vermont (61.4). There was substantial interstate variation in the timing of YLLs and differences in YLLs by gender. YLLs per death increased from 9.2 in the first year of the pandemic to 10.8 through the first 2 years. CONCLUSIONS: Our findings improve our understanding of how the mortality effects of COVID-19 have evolved. This insight can be valuable to public health officials as the disease moves to an endemic phase.

Years of life lost associated with COVID-19 deaths in the USA during the first year of the pandemic.

BACKGROUND: Years of Life Lost (YLLs) measure the shortfall in life expectancy due to a medical condition and have been used in multiple contexts. Previously it was estimated that there were 1.2 million YLLs associated with coronavirus disease 2019 (COVID-19) deaths in the USA through 11 July 2020. The aim of this study is to update YLL estimates for the first full year of the pandemic. METHODS: We employed data regarding COVID-19 deaths in the USA through 31 January 2021 by jurisdiction, gender and age group. We used actuarial life expectancy tables by gender and age to estimate YLLs. RESULTS: We estimated roughly 3.9 million YLLs due to COVID-19 deaths, which correspond to roughly 9.2 YLLs per death. We observed a large range across states in YLLs per 10 000 capita, with New York City at 298 and Vermont at 12. Nationally, the YLLs per 10 000 capita were greater for males than females (136.3 versus 102.3), but there was significant variation in the differences across states. CONCLUSIONS: Our estimates provide further insight into the mortality effects of COVID-19. The observed differences across states and genders demonstrate the need for disaggregated analyses of the pandemic's effects.

Outbreak of Multidrug-Resistant Salmonella Heidelberg Infections Linked to Dairy Calf Exposure, United States, 2015-2018.

In August 2016, the Wisconsin Department of Health Services notified the U.S. Centers for Disease Control and Prevention of multidrug-resistant (MDR) Salmonella enterica serovar Heidelberg infections in people who reported contact with dairy calves. Federal and state partners investigated this to identify the source and scope of the outbreak and to prevent further illnesses. Cases were defined as human Salmonella Heidelberg infection caused by a strain that had one of seven pulsed-field gel electrophoresis (PFGE) patterns or was related by whole genome sequencing (WGS), with illness onset from January 1, 2015, through July 2, 2018. Patient exposure and calf purchase information was collected and analyzed; calves were traced back from the point of purchase. Isolates obtained from animal and environmental samples collected on-farm were supplied by veterinary diagnostic laboratories and compared with patient isolates using PFGE and WGS. Antimicrobial susceptibility testing by standardized broth microdilution was performed. Sixty-eight patients from 17 states were identified. Forty (63%) of 64 patients noted cattle contact before illness. Thirteen (33%) of 40 patients with exposure to calves reported that calves were sick or had died. Seven individuals purchased calves from a single Wisconsin livestock market. One hundred forty cattle from 14 states were infected with the outbreak strain. WGS indicated that human, cattle, and environmental isolates from the livestock market were genetically closely related. Most isolates (88%) had resistance or reduced susceptibility to antibiotics of ≥5 antibiotic classes. This resistance profile included first-line antibiotic treatments for patients with severe salmonellosis, including ampicillin, ceftriaxone, and ciprofloxacin. In this outbreak, MDR Salmonella Heidelberg likely spread from sick calves to humans, emphasizing the importance of illness surveillance in animal populations to prevent future spillover of this zoonotic disease.

Modeling the Effect of Tylosin Phosphate on Macrolide-Resistant Enterococci in Feedlots and Reducing Resistance Transmission.

Tylosin phosphate (TYL) is administered to more than 50% of U.S. beef cattle to reduce the incidence of liver abscesses but may increase the risk of macrolide-lincosamide-streptogramin-resistant bacteria disseminating from the feedlot. Limited evidence has been collected to understand how TYL affects the proportion of resistant bacteria in cattle or the feedlot environment. We created a mathematical model to investigate the effects of TYL administration on Enterococcus dynamics and examined preharvest strategies to mitigate the impact of TYL administration on resistance. The model simulated the physiological pharmacokinetics of orally administered TYL and estimated the pharmacodynamic effects of TYL on populations of resistant and susceptible Enterococcus within the cattle large intestine, feedlot pen, water trough, and feed bunk. The model parameters' population distributions were based on the available literature; 1000 Monte Carlo simulations were performed to estimate the likely distribution of outcomes. At the end of the simulated treatment period, the median estimated proportion of macrolide-resistant enterococci was only 1 percentage point higher within treated cattle compared with cattle not fed TYL, in part because the TYL concentrations in the large intestine were substantially lower than the enterococci minimum inhibitory concentrations. However, 25% of the simulated cattle had a >10 percentage point increase in the proportion of resistant enterococci associated with TYL administration, termed the TYL effect. The model predicts withdrawing TYL treatment and moving cattle to an antimicrobial-free terminal pen with a low prevalence of resistant environmental enterococci for as few as 6 days could reduce the TYL effect by up to 14 percentage points. Additional investigation of the importance of this subset of cattle to the overall risk of resistance transmission from feedlots will aid in the interpretation and implementation of resistance mitigation strategies.

Years of life lost associated with COVID-19 deaths in the United States.

BACKGROUND: The mortality effects of COVID-19 are a critical aspect of the disease's impact. Years of life lost (YLLs) can provide greater insight than the number of deaths by conveying the shortfall in life expectancy and thus the age profile of the decedents. METHODS: We employed data regarding COVID-19 deaths in the USA by jurisdiction, gender and age group for the period 1 February 2020 through 11 July 2020. We used actuarial life expectancy tables by gender and age to estimate YLLs. RESULTS: We estimated roughly 1.2 million YLLs due to COVID-19 deaths. The YLLs for the top six jurisdictions exceeded those for the remaining 43. On a per-capita basis, female YLLs were generally higher than male YLLs throughout the country. CONCLUSIONS: Our estimates offer new insight into the effects of COVID-19. Our findings of heterogenous rates of YLLs by geography and gender highlight variation in the magnitude of the pandemic's effects that may inform effective policy responses.

Psychopharmacology Utilization Among Children with Anxiety and Obsessive-Compulsive and Related Disorders Following Hurricane Katrina.

This study aimed to examine the impact of Hurricane Katrina exposure on medication utilization among children with pre-existing anxiety and obsessive-compulsive and related disorders (OCRDs). Medicaid claims data from 2004 to 2006 were analyzed. Children with pre-existing anxiety/OCRDs were compared as a function of those living in a Louisiana disaster area, Louisiana non-disaster area, or Texas in terms of filled prescriptions and average days medication supply. This was further examined as a function of disorder/medication type. Prescriptions filled and average days medication supply were lower for those who resided in the disaster area of Louisiana relative to non-disaster zones in Texas (but not Louisiana). Children with OCD who lived in a disaster zone in Louisiana had 16.6 fewer days supply of antidepressants relative to youth in Texas. Similarly, children with PTSD who lived in a disaster zone in Louisiana had approximately 7 fewer days supply of stimulant medication relative to those who lived in Texas. Medication utilization was reduced for those youth directly exposed to Katrina relative to children in Texas, suggesting potential service disruption. Children with OCD and PTSD may be more likely to experience treatment disruption. Following disasters, particular attention should be given to ensuring continued treatment access for youth with pre-existing anxiety and OCRDs (as well as other conditions).

An Organizational Intervention to Reduce Physician Burnout.

EXECUTIVE SUMMARY: Burnout is an individual's specific, personal, and intimate stress reaction to the workplace, characterized by emotional exhaustion, depersonalization, and reduced self-efficacy. Even though it particularly affects the helping professions, there has been relatively little exploration into the causes and determinants of burnout among physicians; instead, the focus has been on documenting the prevalence and consequences of physician burnout. Furthermore, while the theory of burnout is based on the relationship between the individual and his or her workplace, interventions have focused on improving the resilience of an individual to withstand this imbalance rather than identifying and ameliorating the cause.This study observed a natural experiment to measure changes in primary care providers' burnout before and after the implementation of a workload intervention that changed the work process within primary care clinics. Four clinics received the intervention, while four others served as comparisons. Among physicians in clinics receiving the intervention, the results show significant impacts, with an improvement in workload of 0.61 units (p = 0.037) and a decrease in the emotional exhaustion dimension of burnout of 6.989 units (p = 0.039).Self-care interventions are inconsistent with the theory of burnout; success of such interventions may be due to participants self-selecting these interventions, and individuals' inability to change their workplace without management approval. Leaders need to consider the impact of the workplace itself on physicians, in addition to results or outcomes.

Contemporary issues in anaphylaxis and the evolution of epinephrine autoinjectors: What will the future bring?

BACKGROUND: Food allergy and anaphylaxis appear to be increasing in the United States, especially in young children, and preparedness is paramount to successful emergency management in the community. Although the treatment of choice for anaphylaxis is epinephrine delivered by autoinjection, some devices are challenged by less user-friendly designs or pose the risk of injury, especially in young patients. Human factors engineering has played a larger role in the development of more recent epinephrine autoinjector technologies and will continue to play a role in the evolution and future design of epinephrine autoinjectors. OBJECTIVE: To discuss contemporary issues related to the identification and management of anaphylaxis, current and future epinephrine autoinjector design, and unmet needs for the treatment of special populations, namely, young children weighing less than 15 kg. METHODS: The literature was reviewed and select articles retrieved to support expert clinical opinions on the need for improved recognition of anaphylaxis, epinephrine autoinjector design, and unmet needs in special populations. RESULTS: Anaphylaxis may be underrecognized and poorly defined in infant- and toddler-aged children, current devices may not be adequate to safely treat these patients (ie, inappropriate needle length), and health care professionals may not be aware of these issues. CONCLUSION: As epinephrine autoinjector technology continues to evolve, device characteristics that promote safe, user-friendly experiences and give clinicians and their patients confidence to successfully treat anaphylaxis during an emergency, without injury, will be favored.

Cost-Effectiveness of Integrating a Clinical Decision Rule and Staged Imaging Protocol for Diagnosis of Appendicitis.

OBJECTIVE: To evaluate the cost-effectiveness of a diagnostic protocol for appendicitis in children, the use of a validated clinical decision rule (CDR) and a staged imaging protocol, compared with usual care. METHODS: We estimated the cost-effectiveness of the three competing strategies using parameters from existing literature as well as a Markov model developed to simulate the effects of exposure to ionizing radiation from a single computed tomography (CT) study in the course of diagnosis. The simulation model was applied to a hypothetical cohort of 100,000 boys and girls, age 10 years, presenting with acute abdominal pain to emergency departments in the United States. RESULTS: The integrated strategy, the CDR followed by staged imaging, was found to be the most cost-effective approach. Cost savings accrued from the reduction in CT utilization for low-risk patients compared with the other two strategies. The addition of ultrasound (US) to the CDR strategy reduced CT utilization by an additional 10.9%, its main cost advantage, with negligible change in net health benefits from false-negative US results, and associated morbidity or mortality. CONCLUSIONS: Results suggest that the integration of staged imaging with the CDR for the diagnosis of appendicitis in children is a cost-effective and cost-saving approach. The model estimates a further 10.9% reduction in the number of CTs from the incorporation of US for patients scoring high or medium risk, in excess of the 19.5% reduction estimated in the CDR validation study.

The influence of organization tenure on nurses' perceptions of multiple work process improvement initiatives.

BACKGROUND: A nurse's optimism or skepticism toward an organization-mandated change initiative largely depends on their experience with similar change initiatives and their unit's and organization's track record with previous change efforts. Thus, depending on the context, organization tenure can work in favor or against any particular change initiative. However, few studies have examined the impact of organization tenure on perceptions toward change initiatives. The few studies that have been conducted have yielded mixed results and have only targeted single or similar work initiatives. PURPOSE: The aim of this study was to examine how organization tenure impacts nurses' perceptions toward a diverse array of work process improvement initiatives. METHODOLOGY: The data are derived from a survey of 421 medical-surgical nurses representing 41 units across four hospitals. The survey was designed to capture nurses' perceptions toward three change initiatives-AIDET (Acknowledge, Introduce, Duration, Explanation, and Thank You), hourly rounding, and discharge phone calls-and their impact across two subscales-patient care and individual work change. FINDINGS: Organization tenure is significantly and negatively associated with change receptivity for the non-patient safety-oriented initiative (AIDET). This negative relationship dissipates as we evaluate more patient safety-oriented work process initiatives (hourly rounding and discharge phone calls). PRACTICE IMPLICATIONS: Significant differences in nurses' perceptions toward change do exist depending on how long they have worked for their employer. For non-patient safety-oriented change initiatives, veteran-to-the-organization nurses may exhibit more recalcitrance than their new-to-the-organization counterparts. However, our findings also suggest the presence of a patient safety exception rule where veteran-to-the-organization nurses do not exhibit differences in opinion than their new-to-the-organization counterparts for patient safety-oriented change initiatives.

An important role for mitochondrial antiviral signaling protein in the Kaposi's sarcoma-associated herpesvirus life cycle.

UNLABELLED: Kaposi's sarcoma-associated herpesvirus (KSHV) has been shown to be recognized by two families of pattern recognition receptors (PRRs), Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Here we show that MAVS and RIG-I (retinoic acid-inducible gene 1), an RLR family member, also have a role in suppressing KSHV replication and production. In the context of primary infection, we show that in cells with depleted levels of MAVS or RIG-I, KSHV transcription is increased, while beta interferon (IFN-ß) induction is attenuated. We also observed that MAVS and RIG-I are critical during the process of reactivation. Depletion of MAVS and RIG-I prior to reactivation led to increased viral load and production of infectious virus. Finally, MAVS depletion in latent KSHV-infected B cells leads to increased viral gene transcription. Overall, this study suggests a role for MAVS and RIG-I signaling during different stages of the KSHV life cycle. IMPORTANCE: We show that RIG-I and its adaptor protein, MAVS, can sense KSHV infection and that these proteins can suppress KSHV replication following primary infection and/or viral reactivation.

Burnout Among Primary Care Physicians: A Test of the Areas of Worklife Model.

Examinations of the current state of the physician workforce, in the United States and globally, indicate a declining overall well-being, and specifically increasing levels of burnout. The consequences of these effects include early retirements or exits from the medical profession, difficulties improving the patient experience, and low levels of provider engagement with clinic-level and system-level initiatives. Such consequences affect physicians, healthcare organizations, and patients. While most research has focused on identifying burnout, cataloging its effects, and creating a case for attending to its impact, relatively few studies have focused on exploring the antecedents of burnout for physicians. The goal of this study was to test an etiological model, the Areas of Worklife Scale (AWS), for practicing primary care physicians. Using the AWS and the Maslach Burnout Inventory, the study used a longitudinal survey research design method to query primary care physicians employed at a large integrated delivery system in the United States. Data collected successfully fit the AWS model for burnout among primary care physicians, supporting our theory that workplace drivers are responsible for burnout. Workload, control, and values congruence are the largest drivers of burnout for practicing primary care physicians. The AWS model provides key insights into the domains of work that cause stress and ultimately burnout for physicians, and these domains can guide physicians and managers to develop interventions to fight the rising incidence of burnout.

The viral interferon regulatory factors of kaposi's sarcoma-associated herpesvirus differ in their inhibition of interferon activation mediated by toll-like receptor 3.

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is correlated with three human malignancies and can establish lifelong latent infection in multiple cell types within its human host. In order to establish and maintain infection, KSHV utilizes multiple mechanisms to evade the host immune response. One such mechanism is the expression of a family of genes with homology to cellular interferon (IFN) regulatory factors (IRFs), known as viral IRFs (vIRFs). We demonstrate here that KSHV vIRF1, -2, and -3 have a differential ability to block type I interferon signaling mediated by Toll-like receptor 3 (TLR3), a receptor we have previously shown to be activated upon KSHV infection. vIRF1, -2, and -3 inhibited TLR3-driven activation of IFN transcription reporters. However, only vIRF1 and vIRF2 inhibited increases in both IFN-ß message and protein levels following TLR3 activation. The expression of vIRF1 and vIRF2 also allowed for increased replication of a virus known to activate TLR3 signaling. Furthermore, vIRF1 and vIRF2 may block TLR3-mediated signaling via different mechanisms. Altogether, this report indicates that vIRFs are able to block IFN mediated by TLRs but that each vIRF has a unique function and mechanism for blocking antiviral IFN responses.

Bedside shift reports: what does the evidence say?

Bedside shift reports are viewed as an opportunity to reduce errors and important to ensure communication between nurses and communication. Models of bedside report incorporating the patient into the triad have been shown to increase patient engagement and enhance caregiver support and education. Nurse shift reports and nurse handovers are 2 of the most critical processes in patient care that can support patient safety and reduce medical errors in the United States. Nurses continue to not recognize the evidence supporting this practice and adopt bedside report into practice.

Latent Kaposi's sarcoma-associated herpesvirus infection of monocytes downregulates expression of adaptive immune response costimulatory receptors and proinflammatory cytokines.

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is associated with the development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. We report the establishment of a monocytic cell line latently infected with KSHV (KSHV-THP-1). We profiled viral and cytokine gene expression in the KSHV-THP-1 cells compared to that in uninfected THP-1 cells and found that several genes involved in the host immune response were downregulated during latent infection, including genes for CD80, CD86, and the cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß). Thus, KSHV minimizes its immunological signature by suppressing key immune response factors, enabling persistent infection and evasion from host detection.

Adding decision models to systematic reviews: informing a framework for deciding when and how to do so.

OBJECTIVE: Decision models are sometimes used alongside systematic reviews to synthesize evidence. Clarity, however, is lacking about when and how to conduct modeling studies in tandem with systematic reviews, as well as about how to evaluate and present model results. The objective of this study was to collect and analyze information from various sources to inform the development of a framework for deciding when and how a decision model should be added to a systematic review. METHODS: We collected data through 1) review and analysis of evidence reports that used decision models; 2) review and synthesis of current best practices for the development of decision models; 3) interviews of Evidence-Based Practice Center directors and selected staff, United States Preventive Services Task Force members, and decision modelers who developed models used by the United States Preventive Services Task Force; and 4) a focus group of expert modelers. RESULTS: Models are well suited to address gaps in the literature, better suited for certain types of research questions, and essential for determining the value of information relating to future research. Opinions differ regarding whether model outputs constitute evidence, but interviewees expressed concern over the lack of standards and directions in grading and reporting such "evidence." Interviews of stakeholders and modelers revealed the importance of communication and presentation of model results as well as the importance of model literacy and involvement of stakeholders. CONCLUSIONS: The study demonstrates the need for a framework for deciding when and how to use models alongside systematic reviews and provides information to develop such a framework.

Cost-effectiveness analysis of radiosurgical capsulotomy versus treatment as usual for treatment-resistant obsessive-compulsive disorder.

OBJECTIVE: Stereotactic radiosurgical capsulotomy (SRS-C) is an effective neurosurgical option for patients with treatment-resistant obsessive-compulsive disorder (TROCD). Unlike other procedures such as deep brain stimulation and radiofrequency ablation, the cost-effectiveness of SRS-C for TROCD has not been investigated. The authors herein report the first cost-effectiveness analysis of SRS-C for TROCD. METHODS: Using a decision analytic model, the authors compared the cost-effectiveness of SRS-C to treatment as usual (TAU) for TROCD. Treatment response and complication rates were derived from a review of relevant clinical trials. Published algorithms were used to convert Yale-Brown Obsessive Compulsive Scale scores into utility scores reflecting improvements in quality of life. Costs were approached from the healthcare sector perspective and were drawn from Medicare reimbursement rates and available healthcare economics data. A Monte Carlo simulation and probabilistic sensitivity analysis were performed to estimate the incremental cost-effectiveness ratio. RESULTS: One hundred fifty-eight TROCD patients across 9 studies who had undergone SRS-C and had at least 36 months of follow-up were included in the model. Compared to TAU, SRS-C was more cost-effective, with an estimated incremental cost-effectiveness ratio of $28,960 per quality-adjusted life year (QALY) gained. Within the 3-year time horizon, net QALYs gained were greater in the SRS-C group than the TAU group by 0.27 (95% CI 0.2698-0.2702, p < 0.0001). At willingness-to-pay thresholds of $50,000 and $100,000 per QALY, the Monte Carlo simulation revealed that SRS-C was more cost-effective than TAU in 83% and 100% of iterations, respectively. CONCLUSIONS: Compared to TAU, SRS-C for TROCD is more cost-effective under a range of possible cost and effectiveness values.

Activation of plasmacytoid dendritic cells by Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with multiple human malignancies, including Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Following primary infection, KSHV typically goes through a brief period of lytic replication prior to the establishment of latency. Plasmacytoid dendritic cells (pDCs) are the major producers of type 1 interferon (IFN), primarily in response to virus infection. Toll-like receptors (TLRs) are key components of the innate immune system, and they serve as pathogen recognition receptors that stimulate the host antiviral response. pDCs express exclusively TLR7 and TLR9, and it is through these TLRs that the type 1 interferon response is activated in pDCs. Currently, it is not known whether KSHV is recognized by pDCs and whether activation of pDCs occurs in response to KSHV infection. We now report evidence that KSHV can infect human pDCs and that pDCs are activated upon KSHV infection, as measured by upregulation of CD83 and CD86 and by IFN-α secretion. We further show that induction of IFN-α occurs through activation of TLR9 signaling and that a TLR9 inhibitor diminishes the production and secretion of IFN-α by KSHV-infected pDCs.

Toll-like receptor signaling controls reactivation of KSHV from latency.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Like other herpesviruses, KSHV establishes life-long latency in the human host with intermittent periods of reactivation. Physiological triggers of herpesviral reactivation are poorly defined. Toll-like receptors (TLRs) recognize pathogens and are vital for the host innate immune response. We screened multiple TLR agonists for their ability to initiate KSHV replication in latently infected PEL. Agonists specific for TLR7/8 reactivated latent KSHV and induced viral lytic gene transcription and replication. Furthermore, vesicular stomatitis virus (VSV), a bonafide physiological activator of TLR7/8, also reactivated KSHV from latency. This demonstrates that secondary pathogen infection of latently infected cells can reactivate KSHV. Human herpesviruses establish life-long latency in the host, and it is plausible that a latently infected cell will encounter multiple pathogens during its lifetime and that these encounters lead to episodic reactivation. Our findings have broad implications for physiological triggers of latent viral infections, such as herpesviral reactivation and persistence in the host.