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Background High levels of catecholamines are cardiotoxic and associated with stress‐induced cardiomyopathies. Using a septic shock model that reproduces the reversible cardiomyopathy seen over 10 days associated with human septic shock, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac dysfunction. Methods and Results Purpose‐bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6). The septic animals were than randomized to epinephrine (1 μg/kg per minute, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging, catecholamine levels, and troponins were collected over 92 hours. Serial adenosine‐stress perfusion cardiac magnetic resonance imaging was performed on septic animals randomized to receive saline (n=8 out of 15) or epinephrine (n=8 out of 15). High‐dose sedation was given to suppress endogenous catecholamine release. Despite catecholamine levels largely remaining within the normal range throughout, by 48 hours, septic animals receiving saline versus nonseptic animals still developed significant worsening of left ventricular ejection fraction, circumferential strain, and ventricular‐aortic coupling. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800‐fold, but epinephrine produced no significant further worsening of left ventricular ejection fraction, circumferential strain, or ventricular‐aortic coupling. Septic animals receiving saline had a significant increase in microcirculatory reserve without troponin elevations. Septic animals receiving epinephrine had decreased edema, blunted microcirculatory perfusion, and elevated troponin levels that persisted for hours after the epinephrine infusion stopped. Conclusions Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion‐induced ischemia. However, epinephrine itself has potentially harmful long‐lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion.

Background Septic shock is associated with increases in end‐diastolic volume (EDV) and decreases in ejection fraction that reverse within 10 days. Nonsurvivors do not develop EDV increases. The mechanism is unknown. Methods and Results Purpose‐bred beagles (n=33) were randomized to receive intrabronchial Staphylococcus aureus or saline. Over 96 hours, cardiac magnetic resonance imaging and echocardiograms were performed. Tissue was obtained at 66 hours. From 0 to 96 hours after bacterial challenge, septic animals versus controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%). On histology, the major finding was nonocclusive microvascular injury with edema in myocytes, the interstitium, and endothelial cells. Edema was associated with significant worsening of biventricular ejection fractions, ventricular‐arterial coupling, and circumferential strain. Early during sepsis, (0–24 hours), the EDV decreased; significantly more in nonsurvivors (ie, greater diastolic dysfunction). From 24 to 48 hours, septic animals' biventricular chamber sizes increased; in survivors significantly greater than baseline and nonsurvivors, whose EDVs were not different from baseline. Preload, afterload, or heart rate differences did not explain these differential changes. Conclusions The cardiac dysfunction of sepsis is associated with wall edema. In nonsurvivors, at 0 to 24 hours, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part, explain the EDV increases from 24 to 48 hours because of a potentially reparative process removing damaged wall tissue. Septic cardiomyopathy is most consistent with a nonocclusive microvascular injury resulting in edema causing reversible systolic and diastolic dysfunction with more severe diastolic dysfunction being associated with a decreased EDV and death.

Tomislav M Jelic,1 Oscar C Estalilla,1 Jeffrey A Vos,2 Gary Harvey,1 Caitlin J Stricker,1 Ayodele O Adelanwa,2 Ahmed A Khalid,3 Milton J Plata1 1Department of Pathology and Laboratory Medicine, Charleston Area Medical Center, Charleston, WV, USA; 2Department of Pathology, Anatomy and Laboratory Medicine, West Virginia University School of Medicine, Morgantown, WV, USA; 3Cancer Center, Charleston Area Medical Center, Charleston, WV, USACorrespondence: Tomislav M Jelic, Charleston Area Medical Center, Department of Pathology and Laboratory Medicine, 3200 MacCorkle Avenue, Charleston, WV, 25304, USA, Tel +1 304 546 6714, Email tomilsav.jelic@suddenlink.netBackground and Aims: Significance of absolute number of CD34+ cells in the peripheral blood of patients with less than 1% myeloblasts by manual differential count is unknown and our aim is to study its relevance in clinical practice.Methods: We studied 138 peripheral bloods flow cytometric analyses in patients with less than 1% myeloblasts by manual differential, when CD34+ events were present in the gate that encompassed lymphocytes, monocytes, stem cells, and blasts.Results: The average absolute number of CD34+cells in the peripheral blood was 11 CD34+cells/μL ranging from less than 1 cell/μL to 147 cells/μL. The average absolute number of CD34+ cells in patients with an abnormal expansive process involving bone marrow (metastases, myelodysplasia, granulomas, marrow infections) or if bone marrow biopsy not performed, presumed expansive marrow process was 25 cells/μL, and in patients without an expansive marrow process (or presumed negative) was 4 cells/μL (P< 0.00007). Cutoff 12 CD34+ cells/μL had 93% positive predictive value for bone marrow involvement by an expansive process and 78% negative predictive value.Conclusion: Flow cytometric testing of the peripheral blood is extremely sensitive method for enumerating CD34+ cells and can detect fewer than one CD34+ cell/μL. The absolute number of CD34+ cells in the peripheral blood is a useful parameter in determining marrow involvement by an expansive process and may provide guidance with respect to the necessity for bone marrow biopsy.Keywords: flow cytometry, CD34 positive cells, peripheral blood, myeloblasts, bone marrow biopsy

Habtam Areri, 1, 2 Amy Marshall, 1 Gillian Harvey 1 1Adelaide Nursing School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia; 2School of Nursing and Midwifery, College of Health Sciences, Addis Ababa University, Addis Ababa 4412, EthiopiaCorrespondence: Habtam Areri Tel +251 910218513Email habera76@gmail.comBackground: The changing nature of HIV from an acute to chronic illness requires adults living with HIV to self-manage. Self-management enables individuals with HIV to maintain physical health, medication adherence and live with HIV-related conditions. This study aimed to explore self-management experiences of adults living with HIV on antiretroviral therapy in Ethiopia.Methods: A qualitative descriptive study framed by the Individual and Family Self-Management Theory was carried out to explore the self-management experience of adults living with HIV in Northwest Ethiopia. Eleven semi-structured, in-depth interviews were conducted. The recruitment involved participants who volunteered to be contacted during a preceding quantitative study. The interview data were coded inductively and subject to thematic analysis.Results: The main themes identified, each with a number of sub-themes, related to perceptions and experience of self-management, barriers and facilitators of self-management. Factors influencing self-management behaviour were inter-connected and particularly influenced by spiritual practices, low levels of income and experiences of stigma and discrimination.Conclusion: The study highlights barriers to self-management among individuals living with HIV on antiretroviral therapy in a resource-constrained country. Interventions to address modifiable barriers and build on identified facilitators of self-management include working with the broader community to minimise HIV-related stigma and discrimination and engaging with religious leaders to tackle the observed conflict between spiritual practice and effective self-management behaviour.Keywords: self-management, barriers, facilitators, antiretroviral therapy, stigma ; discrimination

Abstract Citalopram prevents serotonin (5-HT) uptake into platelets by blocking the serotonin reuptake transporter (SERT). Although some clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) may affect haemostasis and thrombosis, these poorly-characterised effects are not well understood mechanistically and useful in vitro data is limited. We sought to determine whether the inhibitory effects of citalopram on platelets are mediated via its pharmacological inhibition of 5-HT transport. We quantified the inhibitory potency of (RS)-, (R)- and (S)-citalopram on platelet function. If SERT blockade is the primary mechanism for citalopram-mediated platelet inhibition, these potencies should show quantitative congruence with inhibition of 5-HT uptake. Our data show that citalopram inhibits platelet aggregation, adhesion and thromboxane production with no difference in potency between (R)- and (S)-isomers. By contrast, citalopram had a eudysmic ratio of approximately 17 (S > R) for SERT blockade. Furthermore, nanomolar concentrations of citalopram inhibited 5-HT uptake into platelets but had no effect on other platelet functions, which were inhibited by micromolar concentrations. Our data indicate that citalopram-induced inhibition of platelets in vitro is not mediated by blockade of 5-HT transport. This raises a new question for future investigation: by what mechanism(s) does citalopram inhibit platelets?

The finding of toxicity in a meta-analysis of observational clinical studies of transfused longer stored red blood cells (RBC) and ethical issues surrounding aging blood for human studies prompted us to develop an experimental model of RBC transfusion. Transfusing older RBCs during canine pneumonia increased mortality rates. Toxicity was associated with in vivo hemolysis with release of cell-free hemoglobin (CFH) and iron. CFH can scavenge nitric oxide, causing vasoconstriction and endothelial injury. Iron, an essential bacterial nutrient, can worsen infections. This toxicity was seen at commonly transfused blood volumes (2 units) and was altered by the severity of pneumonia. Washing longer-stored RBCs mitigated these detrimental effects, but washing fresh RBCs actually increased them. In contrast to septic shock, transfused longer stored RBCs proved beneficial in hemorrhagic shock by decreasing reperfusion injury. Intravenous iron was equivalent in toxicity to transfusion of longer stored RBCs and both should be avoided during infection. Storage of longer-stored RBCs at 2 °C instead of higher standard temperatures (4−6 °C) minimized the release of CFH and iron. Haptoglobin, a plasma protein that binds CFH and increases its clearance, minimizes the toxic effects of longer-stored RBCs during infection and is a biologically plausible novel approach to treat septic shock.

Objective: Approximately 10-40% of rectal patients have a complete response (CR) to neoadjuvant chemoradiation (CRT), and these patients have improved survival. Thus, non-operative management (watch-and-wait approach) may be an option for select patients. We aimed to identify clinical predictors of complete response following CRT.Methods: Patients treated with definitive chemoradiation for T3-T4, locally unresectable T1-T2, low-lying T2, and/or node-positive rectal cancer from August 2004 to February 2015 were retrospectively reviewed. Most patients were treated with 50.4 Gy radiation and concurrent 5-fluoruracil or capecitabine. Patients were considered to have a CR if surgical pathology revealed ypT0N0M0 (operative management), or if they had no evidence of residual disease on clinical and radiographic assessment (non-operative management). Statistical analysis was carried out to determine predictors of CR and long-term outcomes. Results: Complete records were available on 138 patients. The median follow-up was 24.5 mos. 36 patients (26.3%) achieved a CR; 30/123 operatively managed patients (24.5%) and 6/15 (40%) non-operatively managed patients. None of the 10 patients with mucinous adenocarcinoma achieved a CR. CEA ≥5 μg/L at diagnosis (OR 0.190, 95% CI 0.037-0.971, p=0.046), tumor size ≥3 cm (OR 0.123, 95% CI 0.020-0.745, p=0.023), distance of tumor from the anal verge ≥3 cm (OR 0.091, 95% CI 0.013-0.613, p=0.014), clinically node positive disease at diagnosis (OR 0.201, 95% CI 0.045-0.895, p=0.035), and interval from CRT to surgery ≥8 weeks (OR 5.267, 95% CI 1.068-25.961, p=0.041) were independent predictors of CR. The CR group had longer 3-year distant metastasis-free survival (DMFS) (93.7% vs. 63.7%, p=0.016) and 3-year disease-free survival (DFS) (91.1% vs. 67.8%, p=0.038). 3-year locoregional control (LRC) (96.6% vs. 81.3%, p=0.103) and overall survival (OS) (97.2% vs. 87.5%, p=0.125) were higher in the CR group but this did not achieve statistical significance. CR was not an independent predictor of LRC, DMFS, or DFS.Conclusions: CEA at diagnosis, tumor size, tumor distance from the anal verge, node positivity at diagnosis, and interval from CRT to surgery were predictors of CR. These clinical variables may offer insight into patient selection and timing of treatment response evaluation in the watch-and-wait approach.

BackgroundDuring sepsis, higher plasma cell-free hemoglobin (CFH) levels portend worse outcomes. In sepsis models, plasma proteins that bind CFH improve survival. In our canine antibiotic-treated Staphylococcus aureus pneumonia model, with and without red blood cell (RBC) exchange transfusion, commercial human haptoglobin (Hp) concentrates bound and compartmentalized CFH intravascularly, increased CFH clearance, and lowered iron levels, improving shock, lung injury, and survival. We now investigate in our model how very high CFH levels and treatment time affect Hp's beneficial effects.Materials and methodsTwo separate canine pneumonia sepsis Hp studies were undertaken: one with exchange transfusion of RBCs after prolonged storage to raise CFH to very high levels and another with rapidly lethal sepsis alone to shorten time to treat. All animals received continuous standard intensive care unit supportive care for 96 hours.ResultsOlder RBCs markedly elevated plasma CFH levels and, when combined with Hp therapy, created supraphysiologic CFH-Hp complexes that did not increase CFH or iron clearance or improve lung injury and survival. In a rapidly lethal bacterial challenge model without RBC transfusion, Hp binding did not increase clearance of complexes or iron or show benefits seen previously in the less lethal model.DiscussionHigh-level CFH-Hp complexes may impair clearance mechanisms and eliminate Hp's beneficial effect during sepsis. Rapidly lethal sepsis narrows the therapeutic window for CFH and iron clearance, also decreasing Hp's beneficial effects. In designing clinical trials, dosing and kinetics may be critical factors if Hp infusion is used to treat sepsis.

In this article, we present an intriguing experimental exercise that does not fall foul of improper use of instrumentation. The activity is designed as an electronics exercise where the role of the instruments in the measurement of the RC time constant is considered. Essentially, we study the accuracy and precision of a measurement of the RC time constant in a series circuit with an oscilloscope as a function of the value of the resistor, against the predicted linear model of [tau] = RC. As the value of the resistor approaches the value of the impedance of the oscilloscope, the time constant deviates from the linear model. We show how to adapt the model to account for this and create a mathematical model that agrees with the measurements. It is hoped that such an exercise will solidify a rule of effective use of oscilloscopes--that the resistance of the circuit should be much lower than the impedance of the scope--in the mind of the student.

BackgroundHaemopoietic progenitor cell (HPC) transplantation can cure sickle cell disease. Non-myeloablative conditioning typically results in donor-derived erythrocytes and stable mixed chimerism of recipient-derived and donor-derived leucocytes. Exposure to donor antigens from the HPC graft and new red cell antibodies induced by transfusion can lead to immunohaematological complications. We assessed the incidence of such complications among HPC transplant recipients with sickle cell disease.MethodsThe study population was all patients with sickle cell disease enrolled before March 31, 2015, in the three clinical trials of non-myeloablative HPC transplantation at the National Institutes of Health. We assessed formation of new red cell antibodies after transplantation and red cell incompatibility between donors and recipients.Findings61 patients were enrolled, 42 were HLA matched and 19 were haploidentical. Nine (15%) had immunohaematological complications. Before HPC transplantation, three patients had antibodies incompatible with their donors. After HPC transplantation, new red cell antibodies were seen in six patients (11 alloantibodies and two autoantibodies), among whom three developed antibodies incompatible with donor or recipient red cells and three developed compatible antibodies. The clinical course of complications was highly variable, from no severe effects attributable to antibodies, to sustained reticulocytopenia, to near-fatal haemolysis. We found no significant correlation between immunohaematological complications and graft failure, graft rejection, or death.InterpretationClinical effects ranged from seemingly not clinically important to potentially fatal. In patients with sickle cell disease, donor and recipient red cell phenotypes should be carefully assessed before transplantation to minimise and manage the risk of immunohaematological complications.FundingIntramural Research Program and National Institutes of Health.

Alongside their conventional roles in thrombosis and hemostasis, platelets have long been associated with nonhemostatic pathologies, including tumor cell metastasis. Numerous mechanistic studies have since demonstrated that the direct binding of platelets to intravascular tumor cells promotes key hallmarks of metastasis, including survival in circulation and tumor cell arrest at secondary sites. However, platelets also interact with nonmalignant cells that make up the stromal and immune compartments within both primary and metastatic tumors. This review will first provide a brief historical perspective on platelet contributions to metastatic disease before discussing the emerging roles that platelets play in creating microenvironments that likely support successful tumor cell metastasis. [ABSTRACT FROM AUTHOR]

Background: Comparative effectiveness research is meant to determine which commonly employed medical interventions are most beneficial, least harmful, and/or most costly in a real-world setting. While the objectives for comparative effectiveness research are clear, the field has failed to develop either a uniform definition of comparative effectiveness research or an appropriate set of recommendations to provide standards for the design of critical care comparative effectiveness research trials, spurring controversy in recent years. The insertion of non-representative control and/or comparator arm subjects into critical care comparative effectiveness research trials can threaten trial subjects' safety. Nonetheless, the broader scientific community does not always appreciate the importance of defining and maintaining critical care practices during a trial, especially when vulnerable, critically ill populations are studied. Consequently, critical care comparative effectiveness research trials sometimes lack properly constructed control or active comparator arms altogether and/or suffer from the inclusion of "unusual critical care" that may adversely affect groups enrolled in one or more arms. This oversight has led to critical care comparative effectiveness research trial designs that impair informed consent, confound interpretation of trial results, and increase the risk of harm for trial participants. Methods/Examples: We propose a novel approach to performing critical care comparative effectiveness research trials that mandates the documentation of critical care practices prior to trial initiation. We also classify the most common types of critical care comparative effectiveness research trials, as well as the most frequent errors in trial design. We present examples of these design flaws drawn from past and recently published trials as well as examples of trials that avoided those errors. Finally, we summarize strategies employed successfully in well-designed trials, in hopes of suggesting a comprehensive standard for the field. Conclusion: Flawed critical care comparative effectiveness research trial designs can lead to unsound trial conclusions, compromise informed consent, and increase risks to research subjects, undermining the major goal of comparative effectiveness research: to inform current practice. Well-constructed control and comparator arms comprise indispensable elements of critical care comparative effectiveness research trials, key to improving the trials' safety and to generating trial results likely to improve patient outcomes in clinical practice. [ABSTRACT FROM AUTHOR]

Honors programs typically enroll many students interested in the healthcare field, and honors administrators and faculty do their best to ensure that those students' dreams are fulfilled. With Medical Doctor (MD) program acceptance rates averaging just 6.1%, students need a standout application. Experience has shown that getting accepted into a medical school is more than earning a great GPA and excelling on the MCAT exam; it also requires convincing a committee of professionals that an applicant has the right personal qualities and work ethic to succeed in the field of medicine, and applicants need to highlight their clinical experience as a method of standing out from the crowd. The authors describe an honors program internship for undergraduate students to participate in a unique experience that emulates the third-year curriculum of medical college, referred to as clinical rotations. The full-time, semester-long medical internship becomes an extraordinary and unusual asset on any student's medical school application. Of particular interest is that this program can be adopted by other higher education institutions for a relatively low cost to the college/university, contingent on a committed partnership with an appropriate medical facility. [ABSTRACT FROM AUTHOR]