The infection-tolerant white-footed deermouse tempers interferon responses to endotoxin in comparison to the mouse and rat.

The white-footed deermouse Peromyscus leucopus, a long-lived rodent, is a key reservoir in North America for agents of several zoonoses, including Lyme disease, babesiosis, anaplasmosis, and a viral encephalitis. While persistently infected, this deermouse is without apparent disability or diminished fitness. For a model for inflammation elicited by various pathogens, the endotoxin lipopolysaccharide (LPS) was used to compare genome-wide transcription in blood by P. leucopus, Mus musculus, and Rattus norvegicus and adjusted for white cell concentrations. Deermice were distinguished from the mice and rats by LPS response profiles consistent with non-classical monocytes and alternatively-activated macrophages. LPS-treated P. leucopus, in contrast to mice and rats, also displayed little transcription of interferon-gamma and lower magnitude fold-changes in type 1 interferon-stimulated genes. These characteristics of P. leucopus were also noted in a Borrelia hermsii infection model. The phenomenon was associated with comparatively reduced transcription of endogenous retrovirus sequences and cytoplasmic pattern recognition receptors in the deermice. The results reveal a mechanism for infection tolerance in this species and perhaps other animal reservoirs for agents of human disease.

Lyme disease is an illness caused by bacteria that spread from infected animals to humans through tick bites. While most people fully recover after a week or two of antibiotic treatments, some will continue to experience debilitating symptoms due, potentially, to the way their immune system responded to the infection. In North America, the white-footed deermouse is one of the most common hosts of the Lyme disease bacteria. Despite its name, this rodent is more closely related to hamsters than to the mice or rats most often used in laboratory studies. Unlike mice and humans, however, deermice carrying Lyme disease bacteria do not get sick; in fact, most deermice living in a Lyme disease region will acquire the infection during their lifetimes, but it has little apparent effect on population numbers. These animals can also better tolerate infection from other microbes. To investigate why this is the case, Milovic et al. exposed mice, rats and deermice to a bacterial toxin that triggers inflammation common to encounters with many kinds of microbes. While all species exhibited physical symptoms as a result, blood samples revealed that mice and rats, but not deermice, reacted as if they were infected with viruses as well as bacteria. This was particularly the case for interferons, a group of hormone-like proteins that protect against viruses but can also lead to harmful long-term inflammatory effects. The deermice controlled their interferon responses to the bacterial substance in a way that mice and rats could not. Milovic et al. also checked which genes each species switched on after exposure to the toxin. This revealed that, unlike deer mice, rats and mice turned on some DNA sequences called endogenous retroviruses, which have no role in fighting infection from bacteria but can lead to harmful persistent inflammation. These results provide elements to better understand why recovery from Lyme disease may differ between people, with some patients retaining symptoms long after their infection has abated. They could also help to better grasp why other diseases, such as COVID-19, can be followed by fatigue and other symptoms of ongoing inflammation.

The white-footed deermouse, an infection-tolerant reservoir for several zoonotic agents, tempers interferon responses to endotoxin in comparison to the mouse and rat.

The white-footed deermouse Peromyscus leucopus, a long-lived rodent, is a key reservoir for agents of several zoonoses, including Lyme disease. While persistently infected, this deermouse is without apparent disability or diminished fitness. For a model for inflammation elicited by various pathogens, the endotoxin lipopolysaccharide (LPS) was used to compare genome-wide transcription in blood by P. leucopus, Mus musculus and Rattus norvegicus and adjusted for white cell concentrations. Deermice were distinguished from the mice and rats by LPS response profiles consistent with non-classical monocytes and alternatively-activated macrophages. LPS-treated P. leucopus, in contrast to mice and rats, also displayed little transcription of interferon-gamma and lower magnitude fold-changes in type 1 interferon-stimulated genes. This was associated with comparatively reduced transcription of endogenous retrovirus sequences and cytoplasmic pattern recognition receptors in the deermice. The results reveal a mechanism for infection tolerance in this species and perhaps other animal reservoirs for agents of human disease.

Lyme Disease Agent Reservoirs Peromyscus leucopus and P. maniculatus Have Natively Inactivated Genes for the High-Affinity Immunoglobulin Gamma Fc Receptor I (CD64).

The abundant and widely distributed deermice Peromyscus leucopus and P. maniculatus are important reservoirs for several different zoonotic agents in North America. For the pathogens they persistently harbor, these species are also examples of the phenomenon of infection tolerance. In the present study a prior observation of absent expression of the high-affinity Fc immunoglobulin gamma receptor I (FcγRI), or CD64, in P. leucopus was confirmed in an experimental infection with Borreliella burgdorferi, a Lyme disease agent. We demonstrate that the null phenotype is attributable to a long-standing inactivation of the Fcgr1 gene in both species by a deletion of the promoter and coding sequence for the signal peptide for FcγRI. The Fcgr1 pseudogene was also documented in the related species P. polionotus. Six other Peromyscus species, including P. californicus, have coding sequences for a full-length FcγRI, including a consensus signal peptide. An inference from reported phenotypes for null Fcgr1 mutations engineered in Mus musculus is that one consequence of pseudogenization of Fcgr1 is comparatively less inflammation during infection than in animals, including humans, with undisrupted, fully active genes.

Understanding online ratings of joint arthroplasty surgeons: A national cross-sectional analysis.

Background: Patient reviews provide an important referral source for physicians and an opportunity to improve practice performance. This study's objective was to characterize the online reviews of hip and knee arthroplasty surgeons published by three of the industry's leading platforms. Methods: A random sample of 1000 hip and knee arthroplasty surgeons across all 50 US states (10 hip and 10 knee surgeons per state) was generated using Google Search. A total of 7842 online reviews posted for those surgeons on Healthgrades, Vitals, and Google were analyzed. A range of surgeons, affiliated hospitals, and reviewer attributes was compared to identify significant predictors of patient satisfaction. Results: The study cohort had 98.1% male surgeons with a mean age of 53.55 ± 8.94 years and mean experience of 26.43 ± 9.21 years. Younger age (p < 0.001), shorter years of experience (p < 0.001), and arthroplasty fellowship training (p < 0.001) were associated with more positive ratings. Reviewer anonymity, observed in 30.93% of all reviews, tended to correlate with more negative ratings (p < 0.001). Overall, 86.93% of patient remarks were positive, and only 74.81% of remarks centered on physician attributes. The five leading components of patient satisfaction were perceptions of physician competence (34.81%, p < 0.001), bedside manner (23.83%, p = 0.002), and communication (16.17%, p = 0.94); interactions with physician extenders (14.75%, p < 0.001); and wait time (2.73%, p < 0.001). Conclusion: While most ratings of hip and knee arthroplasty surgeons were positive, more than a quarter of reviews were either not directly related to the individual surgeons or were submitted anonymously. Caution is advised regarding overreliance on patient experience surveys as predictors of physician performance.

Platelet activation and partial desensitization are associated with viral xenophagy in patients with severe COVID-19.

Mild thrombocytopenia, changes in platelet gene expression, enhanced platelet functionality, and presence of platelet-rich thrombi in the lung have been associated with thromboinflammatory complications of patients with COVID-19. However, whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gets internalized by platelets and directly alters their behavior and function in infected patients remains elusive. Here, we investigated platelet parameters and the presence of viral material in platelets from a prospective cohort of 29 patients with severe COVID-19 admitted to an intensive care unit. A combination of specific assays, tandem mass spectrometry, and flow cytometry indicated high levels of protein and lipid platelet activation markers in the plasma from patients with severe COVID-19 associated with an increase of proinflammatory cytokines and leukocyte-platelets interactions. Platelets were partly desensitized, as shown by a significant reduction of αIIbß3 activation and granule secretion in response to stimulation and a decrease of surface GPVI, whereas plasma from patients with severe COVID-19 potentiated washed healthy platelet aggregation response. Transmission electron microscopy indicated the presence of SARS-CoV-2 particles in a significant fraction of platelets as confirmed by immunogold labeling and immunofluorescence imaging of Spike and nucleocapsid proteins. Compared with platelets from healthy donors or patients with bacterial sepsis, platelets from patients with severe COVID-19 exhibited enlarged intracellular vesicles and autophagolysosomes. They had large LC3-positive structures and increased levels of LC3II with a co-localization of LC3 and Spike, suggesting that platelets can digest SARS-CoV-2 material by xenophagy in critically ill patients. Altogether, these data show that during severe COVID-19, platelets get activated, become partly desensitized, and develop a selective autophagy response.

Implementation of French Recommendations for the Prevention and the Treatment of Hospital-acquired Pneumonia: A Cluster-randomized Trial.

BACKGROUND: We determined whether an audit on the adherence to guidelines for hospital-acquired pneumonia (HAP) can improve the outcomes of patients in intensive care units (ICUs). METHODS: This study was conducted at 35 ICUs in 30 hospitals. We included consecutive, adult patients hospitalized in ICUs for 3 days or more. After a 3-month baseline period followed by the dissemination of recommendations, an audit on the compliance to recommendations (audit period) was followed by a 3-month cluster-randomized trial. We randomly assigned ICUs to either receive audit and feedback (intervention group) or participate in a national registry (control group). The primary outcome was the duration of ICU stay. RESULTS: Among 1856 patients enrolled, 602, 669, and 585 were recruited in the baseline, audit, and intervention periods, respectively. The composite measures of compliance were 47% (interquartile range [IQR], 38-56%) in the intervention group and 42% (IQR, 25-53%) in the control group (P = .001). As compared to the baseline period, the ICU lengths of stay were reduced by 3.2 days in the intervention period (P = .07) and by 2.8 days in the control period (P = .02). The durations of ICU stay were 7 days (IQR, 5-14 days) in the control group and 9 days (IQR, 5-20 days) in the intervention group (P = .10). After adjustment for unbalanced baseline characteristics, the hazard ratio for being discharged alive from the ICU in the control group was 1.17 (95% confidence interval, .69-2.01; P = .10). CONCLUSIONS: The publication of French guidelines for HAP was associated with a reduction of the ICU length of stay. However, the realization of an audit to improve their application did not further improve outcomes. CLINICAL TRIALS REGISTRATION: NCT03348579.

Completeness and quality of text paging for subspecialty consult requests.

It is unclear whether previously developed frameworks for effective consultation apply to requests initiated by alphanumeric text page. We assessed a random sample of 210 text paged consult requests for communication of previously described 'essential elements' for effective consultation: reason for consult, level of urgency and requester contact information. Overall page quality was evaluated on a 5-point Likert scale. Over 90% of text paged consult requests included contact information and reason for consult; 14% indicated level of urgency. In ordinal logistic regression, reason for consult was most strongly associated with quality (OR 22.4; 95% CI 8.1 to 61.7), followed by callback number (OR 6.2; 95% CI 0.8 to 49.5), caller's name (OR 5.0; 95% CI 1.9 to 13.1) and level of urgency (OR 3.3; 95% CI 1.6 to 6.7). Results suggest that text paged consult requests often include most informational elements, and that urgency, often missing, may not be as 'essential' for text pages as it was once thought to be.

Thromboembolic events and Covid-19.

The novel Corona virus infection (Covid-19) first identified in China in December 2019 has rapidly progressed in pandemic leading to significant mortality and unprecedented challenge for healthcare systems. Although the clinical spectrum of Covid-19 is variable, acute respiratory failure and systemic coagulopathy are common in severe Covid-19 patients. Lung is an important target of the SARS-CoV-2 virus causing eventually acute respiratory distress syndrome associated to a thromboinflammatory state. The cytokinic storm, thromboinflammation and pulmonary tropism are the bedrock of tissue lesions responsible for acute respiratory failure and for prolonged infection that may lead to multiple organ failure and death. The thrombogenicity of this infectious disease is illustrated by the high frequency of thromboembolic events observed even in Covid-19 patients treated with anticoagulation. Increased D-Dimers, a biomarker reflecting activation of hemostasis and fibrinolysis, and low platelet count (thrombocytopenia) are associated with higher mortality in Covid-19 patients. In this review, we will summarize our current knowledge on the thromboembolic manifestations, the disturbed hemostatic parameters, and the thromboinflammatory conditions associated to Covid-19 and we will discuss the modalities of anticoagulant treatment or other potential antithrombotic options.

Patient and Family Advisory Councils for Research: Recruiting and Supporting Members From Diverse and Hard-to-Reach Communities.

OBJECTIVE: To describe strategies to recruit and support members from hard-to-reach groups on research-focused Patient and Family Advisory Councils (PFACs). BACKGROUND: Ensuring diverse representation of members of research PFACs is challenging, and few studies have given attention to addressing this problem. METHODS: A qualitative study was conducted using 8 focus groups and 19 interviews with 80 PFAC members and leaders, hospital leaders, and researchers. RESULTS: Recruitment recommendations were: 1) utilizing existing networks; 2) going out to the community; 3) accessing outpatient clinics; and 4) using social media. Strategies to support inclusion were: 1) culturally appropriate communication methods; 2) building a sense of community between PFAC members; 3) equalizing roles between community members/leaders; 4) having a diverse PFAC leadership team; and 5) setting transparent expectations for PFAC membership. CONCLUSION: Increasing the diversity of research PFACs is a priority, and it is important to determine how best to engage groups that have been traditionally underrepresented.

Early Massive Pulmonary Embolism After Total Hip Arthroplasty in a Patient With Behcet Disease: A Case Report.

Venous complications in Behcet disease (BD) affect nearly 40% of patients. We describe a woman with BD who presented with a massive bilateral pulmonary embolism 30 hours after total hip arthroplasty. The patient underwent surgical thrombectomy and venoarterial extracorporeal membrane oxygenation. Methotrexate was withheld 15 days before surgery and restarted on postoperative day 2. Immunosuppressive therapy, such as methotrexate, appears to be the most effective prophylactic treatment for venous thrombosis in patients with BD, whereas prophylaxis with low-molecular-weight heparin may be ineffective, as was the situation in our patient. Therefore, continuation of methotrexate perioperatively should be considered in patients with BD. Systematically performing preoperative deep vein thrombosis screening should be also considered. The patient also had diabetes mellitus treated with metformin and sitagliptin preoperatively.

Patient and Family Advisory Councils (PFACs): Identifying Challenges and Solutions to Support Engagement in Research.

OBJECTIVE: The aim was to describe barriers to patient and family advisory council (PFAC) member engagement in research and strategies to support engagement in this context. METHODS: We formed a study team comprising patient advisors, researchers, physicians, and nurses. We then undertook a qualitative study using focus groups and interviews. We invited PFAC members, PFAC leaders, hospital leaders, and researchers from nine academic medical centers that are part of a hospital medicine research network to participate. All participants were asked a standard set of questions exploring the study question. We used content analysis to analyze data. RESULTS: Eighty PFAC members and other stakeholders (45 patient/caregiver members of PFACs, 12 PFAC leaders, 12 hospital leaders, 11 researchers) participated in eight focus and 19 individual interviews. We identified ten barriers to PFAC member engagement in research. Codes were organized into three categories: (1) individual PFAC member reluctance; (2) lack of skills and training; and (3) problems connecting with the right person at the right time. We identified ten strategies to support engagement. These were organized into four categories: (1) creating an environment where the PFAC members are making a genuine and unique contribution; (2) building community between PFAC members and researchers; (3) best practice activities for researchers to facilitate engagement; and (4) tools and training. CONCLUSION: Barriers to engaging PFAC members in research include patients' negative perceptions of research and researchers' lack of training. Building community between PFAC members and researchers is a foundation for partnerships. There are shared training opportunities for PFAC members and researchers to build skills about research and research engagement.

It All Just Clicks: Development of an Inpatient E-Consult Program.

Although the use of electronic consultations (e-consults) in the outpatient setting is commonplace, there is little evidence of their use in the inpatient setting. Often, the only choice hospitalists have is between requesting a time-consuming in-person consultation or requesting an informal, undocumented "curbside" consultation. For a new, remote hospital in our healthcare system, we developed an e-consult protocol that can be used to address simple consultation questions. In the first year of the program, 143 e-consults occurred; the top 5 consultants were infectious disease, hematology, endocrinology, nephrology, and cardiology. Over the first 4 months, no safety issues were identified in chart review audits; to date, no safety issues have been identified through the hospital's incident reporting system. In surveys, hospitalists were universally pleased with the quality of e-consult recommendations, though only 43% of consultantsagreed. With appropriate care for patient selection, e-consults can be used to safely and efficiently provide subspecialty expertise to a remote inpatient site Journal of Hospital Medicine 2017;12:332-334.

Exploring Physician Perspectives of Residency Holdover Handoffs: A Qualitative Study to Understand an Increasingly Important Type of Handoff.

BACKGROUND: The term "holdover admissions" refers to patients admitted by an overnight physician and whose care is then transferred to a new primary team the next morning. Descriptions of the holdover process in internal medicine are sparse. OBJECTIVE: To identify important factors affecting the quality of holdover handoffs at an internal medicine (IM) residency program and to compare them to previously identified factors for other handoffs. DESIGN: We undertook a qualitative study using structured focus groups and interviews. We analyzed data using qualitative content analysis. PARTICIPANTS: IM residents, IM program directors, and hospitalists at a large academic medical center. MAIN MEASURES: A nine-question open-ended interview guide. KEY RESULTS: We identified 13 factors describing holdover handoffs. Five factors-physical space, standardization, task accountability, closed-loop verification, and resilience-were similar to those described in prior handoff literature in other specialties. Eight factors were new concepts that may uniquely affect the quality of the holdover handoff in IM. These included electronic health record access, redundancy, unwritten thoughts, different clinician needs, diagnostic uncertainty, anchoring, teaching, and feedback. These factors were organized into five overarching themes: physical environment, information transfer, responsibility, clinical reasoning, and education. CONCLUSIONS: The holdover handoff in IM is complex and has unique considerations for achieving high quality. Further exploration of safe, efficient, and educational holdover handoff practices is necessary.

Effect of insulin versus triple oral therapy on the progression of hepatic steatosis in type 2 diabetes.

BACKGROUND: Hyperinsulinemia has been associated with hepatic fat deposition and ensuing insulin resistance. It is unknown if treatment with exogenous insulin in patients with type 2 diabetes, who are most prone to hepatic fat accumulation, would promote the occurrence or worsening of nonalcoholic fatty liver disease. METHODS: Patients with treatment-naive type 2 diabetes (N = 16) were treated with insulin and metformin for a 3-month lead-in period, then assigned triple oral therapy (metformin, glyburide, and pioglitazone) or continued treatment with insulin and metformin. Hepatic triglyceride content (HTC)-measured by magnetic resonance spectroscopy, serum lipids, glucose, liver function tests, and inflammatory and thrombotic biomarkers were followed for a median of 31 months. RESULTS: The 45% decline in HTC during the lead-in period persisted through the follow-up period with no difference between treatment groups at the end of the study (5.26 ± 4.21% in the triple oral therapy vs 7.47 ± 7.40% for insulin/metformin), whereas glycemic control was comparable. CONCLUSIONS: Improvements in HTC with initial insulin/metformin therapy persisted through the median 31-month follow-up period regardless of the treatment. More importantly, insulin-based treatment did not appear to promote or worsen nonalcoholic fatty liver disease.