Rapid Systematic Review: The Appropriate Use of Quick Sequential Organ Failure Assessment (qSOFA) in the Emergency Department.

BACKGROUND: The concept of sepsis has recently been redefined by an International Task Force. The task force recommended the use of the quick Sequential Organ Failure Assessment (qSOFA) score instead of Systemic Inflammatory Response Syndrome (SIRS) criteria to identify patients at high risk of mortality from sepsis outside of the intensive care unit, including in emergency departments (EDs). However, the primary outcome for qSOFA is prediction of risk for mortality, which is not the principal outcome measure considered in the ED. From the ED perspective, the priorities are the identification (diagnosis) of the septic patient and then the initiation of time-sensitive, life-saving interventions. METHOD: We performed a structured review of PubMed from January 2012 to December 2018, limited to reports involving human subjects and written in English language and containing relevant keywords. The highest-quality studies were then reviewed in a structured format. We utilized these studies to estimate the sensitivity and specificity of SIRS and qSOFA for diagnosis of sepsis. RESULTS: Thirteen unique articles were identified for further review, and the 11 highest-grade articles (C and D) were determined to be appropriate for inclusion in this review, and the two low-grade articles were excluded (E). CONCLUSIONS: Based on multiple retrospective and few prospective studies, it appears that qSOFA performs poorly in comparison with SIRS as a diagnostic tool for ED patients who may have sepsis or septic shock. However, qSOFA does have a strong prognostic accuracy for mortality in those ED patients already diagnosed with sepsis or septic shock.

BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma.

Follicular lymphoma (FL), an indolent neoplasm caused by a t(14;18) chromosomal translocation that juxtaposes the BCL2 gene and immunoglobulin locus, has a variable clinical course and frequently undergoes transformation to an aggressive lymphoma. Although BCL2 mutations have been previously described, their relationship to FL progression remains unclear. In this study, we evaluated the frequency and nature of BCL2 mutations in 2 independent cohorts of grade 1 and 2 FLs, along with the correlation between BCL2 mutations, transformation risk, and survival. The prevalence of BCL2 coding sequence mutations was 12% in FL at diagnosis and 53% at transformation (P < .0001). The presence of these BCL2 mutations at diagnosis correlated with an increased risk of transformation (hazard ratio 3.6; 95% CI, 2.0-6.2; P < .0001) and increased risk of death due to lymphoma (median survival of 9.5 years with BCL2 mutations vs 20.4 years without; P = .012). In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma. Some mutant Bcl-2 proteins exhibited enhanced antiapoptotic capacity in vitro. Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.

Induced resistance to ofatumumab-mediated cell clearance mechanisms, including complement-dependent cytotoxicity, in chronic lymphocytic leukemia.

Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Posttherapy serum OFA levels correlated inversely with both the amount of pretreatment circulating cell-bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses, and the patients with first-dose reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20- targeted therapy for CLL requires determining an mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells.

Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin α-4-ß-1 (VLA-4) with natalizumab can overcome this resistance.

Rituximab improves the outcome of patients with non-Hodgkin lymphoma, but does not completely eradicate residual B-cell populations in the microenvironment of the bone marrow and lymph nodes. Adhesion to stromal cells can protect B-cells from apoptosis induced by chemotherapy drugs [(cell adhesion-mediated drug resistance (CAM-DR)]. A similar mechanism of resistance to rituximab has not, to our knowledge, been described. We tested the hypothesis that the microenvironment protects malignant B-cells from rituximab-induced apoptosis, and that blocking these interactions with natalizumab, an antibody targeting VLA-4 (integrin alfa-4-beta-1/CD49d), can overcome this protection. VLA-4 is an adhesion molecule constitutively expressed on malignant B-cells and is important for pro-survival signalling in the bone marrow and lymph node microenvironment. The human bone marrow stromal cell line HS-5 was shown to strongly protect B-cell lymphoma cells from rituximab cytotoxicity, suggesting the existence of a stromal cell adhesion-mediated antibody resistance (CAM-AR) mechanism analogous to CAM-DR. Natalizumab decreased B-lymphocyte adherence to fibronectin by 75-95% and partially overcame stromal protection against rituximab and cytotoxic drugs. These pre-clinical findings suggest that the addition of stromal adhesion-disruptive drugs to rituximab-containing therapy could improve treatment efficacy.

Importance of residency program web sites to emergency medicine applicants.

Emergency Medicine (EM) residency program web sites are an important tool that programs use to attract applicants. However, there are only a few studies examining the aspects of a program's web site that are most important to EM applicants. We conducted a cross-sectional study of 142 prospective residency applicants interviewing for an EM position at one of three EM residency programs for the 2003 match. The survey demonstrated that almost all applicants researched EM programs online. The majority (71%) identified geographic location as the most important factor in applying to a specific program. Approximately 40% considered an easily navigated web site as very/moderately important to their application decision-making process. Rotation schedule was also important in applicant decision-making. The Internet is a significant source of information to the majority of applicants in EM. Online information from programs' web sites, although not as significant as geography, influences an applicant's choice of where to apply for a residency position. An easily navigated, complete web site may improve the recruitment of candidates to EM residency programs.

Critical care and emergency medicine.

The delivery of critical care in the emergency department is a growing challenge that faces emergency physicians and intensivists. As emergency departments and intensive care units become increasingly crowded, critically ill patients will remain in the emergency department for longer periods of time. The care provided for critically ill patients during the emergency department stay significantly decreases the progression of organ failure and mortality. Further efforts to improve the quality of critical care in the emergency department would logically further reduce mortality and morbidity. As critical care requires significant resources including time from physicians and nurses, as well as physical resources including space, monitoring equipment, and medications, improving the quality of critical care delivery in the emergency department is not without obstacles. Resources are not limitless and the true goal is finding the point where delivering the best patient care possible occurs within the available resources of the emergency department and the hospital. This article describes the current status of critical care in the emergency department and discusses possible strategies for improvement.

The emergency medicine approach to the evaluation and treatment of pulmonary embolism.

Each year in the United States, up to 900,000 individuals will suffer from acute pulmonary embolism, resulting in an estimated 200,000 to 300,000 hospital admissions. Despite decades of research on the topic, the diagnosis remains elusive in many situations and the fatality rate remains significant. This issue presents a review of the current evidence guiding the emergency medicine approach to the diagnosis and treatment of pulmonary embolism. Key to this approach is the concept of risk stratification: using factors from the history and physical examination, plus ancillary tests, to guide clinical decision making. The pathophysiology of pulmonary embolism and decision-support tools are reviewed, and emergency department management strategies are described.

Complement dependent cytotoxicity in chronic lymphocytic leukemia: ofatumumab enhances alemtuzumab complement dependent cytotoxicity and reveals cells resistant to activated complement.

Complement dependent cytotoxicity (CDC) is an important mechanism of action for monoclonal antibodies (mAbs) used in the treatment of chronic lymphocytic leukemia (CLL). We hypothesized that alemtuzumab (ALM) mediated CDC would be increased by the addition of ofatumumab (OFA). CLL cells from 21 previously untreated patients with progressive disease were tested in vitro for mAb binding, complement activation and CDC. The subpopulation of CDC resistant CLL cells was examined for levels of C3b and C5b-9 binding, and expression of complement regulatory proteins. OFA significantly increased complement activation and CDC in ALM-treated CLL cells, suggesting that combining ALM and OFA could improve clinical outcome in patients with CLL. Approximately 10% of CLL cells were resistant to CDC because of lower levels of complement activation or decreased cytotoxicity of activated complement. Improvement of clinical responses will require determining the mechanisms of CDC resistance and developing methods to overcome this problem.

A Phenomenological Investigation of Women's Experiences With Personal Training.

Personal training is a rapidly growing industry in a country that is in dire need of physical fitness and health improvements. The purpose of this phenomenological study was to better understand women's experiences with personal training. To address the research question, eight female participants ages 24 to 54 years were interviewed using the following phenomenological question: "When you think about your current experience with personal training what stands out for you?" The interviews were conducted, transcribed, and qualitatively analyzed to identify themes in participants' responses. The ground that emerged was positive experience within which existed four figural themes: Relationships, trainer qualities, outcomes, and motivation. Results reveal new insight for professionals in the fitness industry and provide future directions for research in kinesiology and exercise psychology.