HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells.

Infection with human immunodeficiency virus 1 (HIV-1) results in the dissemination of virus to gut-associated lymphoid tissue. Subsequently, HIV-1 mediates massive depletion of gut CD4+ T cells, which contributes to HIV-1-induced immune dysfunction. The migration of lymphocytes to gut-associated lymphoid tissue is mediated by integrin alpha4beta7. We demonstrate here that the HIV-1 envelope protein gp120 bound to an activated form of alpha4beta7. This interaction was mediated by a tripeptide in the V2 loop of gp120, a peptide motif that mimics structures presented by the natural ligands of alpha4beta7. On CD4+ T cells, engagement of alpha4beta7 by gp120 resulted in rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses, which facilitate efficient cell-to-cell spreading of HIV-1.

The use of cefepime for treating AmpC ß-lactamase-producing Enterobacteriaceae.

BACKGROUND: AmpC ß-lactamase-producing organisms are associated with significant morbidity and mortality. Induction of resistance to third-generation cephalosporins after exposure to these agents complicates treatment options and carbapenems are considered optimal therapy. The role of cefepime, however, remains unclear. Our objective was to compare clinical outcomes for patients receiving cefepime compared with meropenem for invasive infections caused by organisms expressing AmpC ß-lactamases. METHODS: Hospitalized patients with blood, bronchoalveolar lavage, or intra-abdominal fluid cultures growing Enterobacter spp, Serratia spp, or Citrobacter spp were evaluated using the cefotetan-boronic acid disk test and the cefotetan-cloxacillin Etest to identify organisms with AmpC ß-lactamase production from February 2010 to January 2011. In patients with organisms hyperproducing AmpC ß-lactamases (positive by both methods), clinical outcomes for patients receiving cefepime or meropenem therapy were compared. To minimize the possibility of treatment selection bias, 1:1 nearest neighbor propensity score matching was performed prior to regression analysis. RESULTS: Of 399 patients meeting eligibility criteria, 96 (24%) had confirmed infections with AmpC ß-lactamase-producing organisms. Propensity score matching of patients infected with AmpC ß-lactamase-positive organisms treated with cefepime or meropenem yielded 32 well-balanced patient pairs with no difference in 30-day mortality (odds ratio, 0.63; 95% confidence interval [CI], .23-2.11; P = .36) or length of hospital stay after infection (relative risk, 0.96; 95% CI, .79-1.26; P = .56) between the 2 groups. CONCLUSIONS: Cefepime may be a reasonable option for the treatment of invasive infections due to AmpC ß-lactamase-producing organisms, particularly when adequate source control is achieved.

Returns After Discharge From the Emergency Department Observation Unit: Who, What, When, and Why?

INTRODUCTION: The number of emergency department observation units (EDOU) and observation stays has continued to increase. Despite this, there is limited data on the characteristics of patients who return unexpectedly to the ED after EDOU discharge. METHODS: We identified the charts of all patients who were admitted to the EDOU of an academic medical center between January 2018-June 2020 and had a return to the ED within 14 days of discharge from the EDOU. Patients were excluded if they were admitted to the hospital from the EDOU, left against medical advice, or died in the EDOU. We manually extracted selected demographic factors, comorbidities, and healthcare utilization data from the charts. Physician reviewers identified return visits thought to be related to the index visit or potentially avoidable. RESULTS: During the study period, there were 176,471 ED visits, 4,179 admissions to the EDOU, and 333 return visits to the ED within 14 days from discharge from the EDOU, representing 9.4% of all patients discharged from the EDOU. We identified a higher rate of return for patients treated for asthma and lower rates of return for patients treated for chest pain or syncope than the overall return rate. Physician reviewers determined that 64.6% of unplanned returns were related to the index visit, and 4.5% were potentially avoidable. Of potentially avoidable visits, 53.3% occurred within 48 hours of discharge, supporting the use of this period as a potential quality metric. While there was no significant difference in the percentage of related return visits between males and females, there was a higher rate of potentially avoidable visits for male patients. CONCLUSION: This study adds to the limited body of literature on EDOU returns, finding an overall return rate of under 10%, with about two-thirds of returns determined to be related to the index visit and <5% considered to be potentially avoidable.

Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.

Activation of a naive T cell is a highly energetic event, which requires a substantial increase in nutrient metabolism. Upon stimulation, T cells increase in size, rapidly proliferate, and differentiate, all of which lead to a high demand for energetic and biosynthetic precursors. Although amino acids are the basic building blocks of protein biosynthesis and contribute to many other metabolic processes, the role of amino acid metabolism in T cell activation has not been well characterized. We have found that glutamine in particular is required for T cell function. Depletion of glutamine blocks proliferation and cytokine production, and this cannot be rescued by supplying biosynthetic precursors of glutamine. Correlating with the absolute requirement for glutamine, T cell activation induces a large increase in glutamine import, but not glutamate import, and this increase is CD28-dependent. Activation coordinately enhances expression of glutamine transporters and activities of enzymes required to allow the use of glutamine as a Krebs cycle substrate in T cells. The induction of glutamine uptake and metabolism requires ERK function, providing a link to TCR signaling. Together, these data indicate that regulation of glutamine use is an important component of T cell activation. Thus, a better understanding of glutamine sensing and use in T cells may reveal novel targets for immunomodulation.

The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1.

Both activated and resting CD4(+) T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin alpha(4)beta(7) (alpha(4)beta(7)), the gut mucosal homing receptor. We find that alpha(4)beta(7)(high) CD4(+) T cells are more susceptible to productive infection than are alpha(4)beta(7)(low-neg) CD4(+) T cells in part because this cellular subset is enriched with metabolically active CD4(+) T cells. alpha(4)beta(7)(high) CD4(+) T cells are CCR5(high) and CXCR4(low); on these cells, alpha(4)beta(7) appears in a complex with CD4. The specific affinity of gp120 for alpha(4)beta(7) provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.

Evaluation of Provider Assessment of Clinical History When Using the HEART Score.

Objective: The HEART Score is a clinically validated risk stratification tool for patients with chest pain. Using five parameters (History, Electrocardiogram, Age, Risk factors, and Troponin), this instrument categorizes patients as low, moderate, or high risk for major adverse cardiac events within six weeks after evaluation. Of these parameters, History is the most subjective, as providers independently assign their level of clinical suspicion. Overestimation of history, and ultimately the HEART Score, can result in increased resource utilization, expense, and patient risk. We sought to evaluate bias in provider assessment of history when determining the HEART Score. Methods: Emergency medicine (EM) and Cardiology providers received surveys with one of two versions of clinical vignettes randomized at the question level and were asked to estimate the history component of the HEART Score. Vignettes differed by age, risk factors, sex, and socioeconomic status (SES), but both versions should have received the same score for history. Statistical analysis was then used to assess differences in history assessment between vignettes. Results: Of the 884 responses analyzed, most providers overestimated the historical portion of the HEART Score when assessing risk factors, patient distress, age, and lower SES. Many underestimated history with knowledge of a previous negative stress test. When controlling for specialty, the universal theme was overestimation by EM providers and underestimation by cardiologists. Despite the presence of hypertension, gender differences, and the appearance of mild distress, cardiologists were more likely to correctly estimate history compared to EM providers. SES consideration generally led to an underestimation of history by cardiologists. These findings were all statistically significant. Conclusion: Our study demonstrates that both EM and cardiology providers overestimate history when considering prognosticators that are frequently viewed as concerning. Further education on proper usage of the HEART Score is needed for more appropriate scoring of history and improved resource allocation for hospital systems.

Review of the Effect of Continuous Use and Limited Reuse of N95 Respirators on Respirator Fit.

Background: Coronavirus disease 2019 (COVID-19) has led to severe shortages of filtering facepiece respirators (FFRs). As a result, extended use, limited reuse, and FFR decontamination have been utilized to extend the life of single-use FFRs. Although some studies have raised concerns that reuse could affect the FFR's ability to form a seal, no comprehensive literature review of the effect of extended use or limited reuse on FFR seal exists. Objective: The goal of this review was to assess the effect of extended use and reuse on respirator fit, with and without decontamination. Methods: Searches of PubMed and Medrxiv yielded 24 papers that included assessment of fit after extended use or limited reuse on a human. One additional handpicked paper was added. Results: Studies report a wide variation in the number of donnings and doffings before fit failure between different models of respirators. Additionally, while seal checks lack sufficient sensitivity to reliably detect fit failures, individuals who failed fit testing were often able to pass subsequent tests by re-positioning the respirator. Even with failure, respirators often maintained a substantially higher level of fit than a surgical mask, so they may still provide a level of protection in crisis settings. Conclusion: Based on currently available data, this literature review was unable to establish a consensus regarding the amount of time a respirator can be worn or the number of uses before fit failure will occur. Furthermore, variations in reuses before fit failure between different models of N95 respirators limit the ability to offer a comprehensive recommendation of greater than one reuse or a specific amount of wear time.

Practical Diagnostic Accuracy of Nasopharyngeal Swab Testing for Novel Coronavirus Disease 2019 (COVID-19).

INTRODUCTION: The novel coronavirus (SARS-CoV-2) is the cause of COVID-19, which has had a devastating international impact. Prior reports of testing have reported low sensitivities of nasopharyngeal polymerase chain reaction (PCR), and reports of viral co-infections have varied from 0-20%. Therefore, we sought to determine the accuracy of nasopharyngeal PCR for COVID-19 and rates of viral co-infection. METHODS: We conducted a retrospective chart review of all patients who received viral testing between March 1, 2020-April 28, 2020. Test results of a complete viral pathogen panel and COVID-19 testing were abstracted. We compared patients with more than one COVID-19 test for diagnostic accuracy against the gold standard of chart review. RESULTS: We identified 1950 patients, of whom 1024 were tested for COVID-19. There were 221 repeat tests for COVID-19. Among patients with a repeat test, COVID-19 swabs had a sensitivity of 84.6% (95% confidence interval (CI), 69.5-94.4%) and a specificity of 99.5% (95%CI, 97-100%) compared to a clinical and radiographic criterion reference by chart review. We found viral co-infection rates of 2.3% in patients without COVID-19 and 6.1% in patients with COVID-19. Rates of co-infection appeared to be related to base rates of infection in the community and not a specific property of COVID-19. CONCLUSION: COVID-19 nasopharyngeal PCR specimens are accurate but have imperfect sensitivity. Repeat testing for high-risk patients should be considered, and presence of an alternative virus should not be used to limit testing for COVID-19 for patients where it would affect treatment or isolation.

Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: The role of percutaneous coronary intervention (PCI) in the management of stable coronary artery disease remains controversial. Given advancements in medical therapies and stent technology over the last decade, we sought to evaluate whether PCI, when added to medical therapy, improves outcomes when compared with medical therapy alone. METHODS AND RESULTS: We performed a systematic review and meta-analysis, searching PubMed, EMBASE, and CENTRAL databases, until January 2012, for randomized clinical trials comparing revascularization with PCI to optimal medical therapy (OMT) in patients with stable coronary artery disease. The primary outcome was all-cause mortality, and secondary outcomes included cardiovascular death, nonfatal myocardial infarction, subsequent revascularization, and freedom from angina. Primary analyses were based on longest available follow-up with secondary analyses stratified by trial duration, with short-term (≤1 year), intermediate (1-5 years), and long-term (≥5 years) time points. We identified 12 randomized clinical trials enrolling 7182 participants who fulfilled our inclusion criteria. For the primary analyses, when compared with OMT, PCI was associated with no significant improvement in mortality (risk ratio [RR], 0.85; 95% CI, 0.71-1.01), cardiac death (RR, 0.71; 95% CI, 0.47-1.06), nonfatal myocardial infarction (RR, 0.93; 95% CI, 0.70-1.24), or repeat revascularization (RR, 0.93; 95% CI, 0.76-1.14), with consistent results over all follow-up time points. Sensitivity analysis restricted to studies in which there was >50% stent use showed attenuation in the effect size for all-cause mortality (RR, 0.93; 95% CI, 0.78-1.11) with PCI. However, for freedom from angina, there was a significant improved outcome with PCI, as compared with the OMT group (RR, 1.20; 95% CI, 1.06-1.37), evident at all of the follow-up time points. CONCLUSIONS: In this most rigorous and comprehensive analysis in patients with stable coronary artery disease, PCI, as compared with OMT, did not reduce the risk of mortality, cardiovascular death, nonfatal myocardial infarction, or revascularization. PCI, however, provided a greater angina relief compared with OMT alone, larger studies with sufficient power are required to prove this conclusively.