CD28 homodimer interface mimetic peptide acts as a preventive and therapeutic agent in models of severe bacterial sepsis and gram-negative bacterial peritonitis.

BACKGROUND: Severe gram-negative bacterial infections and sepsis are major causes of morbidity and mortality. Dysregulated, excessive proinflammatory cytokine expression contributes to the pathogenesis of sepsis. A CD28 mimetic peptide (AB103; previously known as p2TA) that attenuates CD28 signaling and T-helper type 1 cytokine responses was tested for its ability to increase survival in models of polymicrobial infection and gram-negative sepsis. METHODS: Mice received AB103, followed by an injection of Escherichia coli 0111:B4 lipopolysaccharide (LPS); underwent induction E. coli 018:K1 peritonitis induction, followed by treatment with AB103; or underwent cecal ligation and puncture (CLP), followed by treatment with AB103. The effects of AB103 on factors associated with and the lethality of challenge infections were analyzed. RESULTS: AB103 strongly attenuated induction of tumor necrosis factor α and interleukin 6 (IL-6) by LPS in human peripheral blood mononuclear cells. Receipt of AB103 following intraperitoneal injection of LPS resulted in survival among 73% of CD1 mice (11 of 15), compared with 20% of controls (3 of 15). Suboptimal doses of antibiotic alone protected 20% of mice (1 of 5) from E. coli peritonitis, whereas 100% (15 of 15) survived when AB103 was added 4 hours following infection. Survival among mice treated with AB103 12 hours after CLP was 100% (8 of 8), compared with 17% among untreated mice (1 of 6). In addition, receipt of AB103 12 hours after CLP attenuated inflammatory cytokine responses and neutrophil influx into tissues and promoted bacterial clearance. Receipt of AB103 24 hours after CLP still protected 63% of mice (5 of 8). CONCLUSIONS: Single-dose AB103 reduces mortality in experimental models of polymicrobial and gram-negative bacterial infection and sepsis, warranting further studies of this agent in clinical trials.

The novel immunotherapeutic oligodeoxynucleotide IMT504 protects neutropenic animals from fatal Pseudomonas aeruginosa bacteremia and sepsis.

IMT504 is a novel immunomodulatory oligonucleotide that has shown immunotherapeutic properties in early preclinical and clinical studies. IMT504 was tested in a neutropenic rat model of Pseudomonas aeruginosa bacteremia and sepsis. This animal system recapitulates many of the pathological processes found in neutropenic patients with Gram-negative, bacterial infections. The research was conducted in the setting of an academic research laboratory. The test subjects were Sprague-Dawley rats. Animals were rendered neutropenic by administration of cyclophosphamide, colonized with P. aeruginosa by oral feeding, and then randomized to receive IMT504 over a range of doses and treatment regimens representing early and late therapeutic interventions. IMT504 immunotherapy conferred a significant survival advantage over the 12-day study period compared with the results seen with placebo-treated animals when the therapy was administered at the onset of neutropenia and even in the absence of antibiotics and after the onset of fever and systemic infection. Notably, even late salvage IMT504 monotherapy was highly effective (13/14 surviving rats with IMT504 therapy versus 2/14 controls, P=<0.001). Moreover, late salvage IMT504 monotherapy was as effective as antibiotic therapy (13/14 surviving rats versus 21/21 rats, P=0.88). In addition, no antagonism or loss of therapeutic efficacy was noted with combination therapy of IMT504 plus antibiotics. IMT504 immunotherapy provides a remarkable survival advantage in bacteremia and sepsis in neutropenic animals and deserves further study as a new treatment option in patients with, or at risk for, severe Gram-negative bacterial infections and sepsis.

Medications and Supplements Prescription Patterns during COVID 19 Pandemic in Yemen: A Questionnaire-Based Study.

Introduction: the study aims to better understand the COVID-19 prescription treatments and over the counter regimens in Yemen in view of limited published data and limited availability of COVID-19 testing. Methods: A 34 question web-based survey was distributed on social media outlets targeting people in Yemen. Data aggregation, analysis, and visualization were performed using Tableau and Microsoft Excel. Results: 2341 individuals reported symptoms concerning for COVID-19 infection, with 25.4% reporting a chronic medical condition. Female patients were less likely to receive medications for treatment in all age groups examined. Azithromycin was the most prescription medication prescribed (32.8%) and vitamin C being the most supplement used (62%). Around 5.5% were on Hydroxychloroquine prophylaxis prior to their diagnosis and only 12.9% of them continued using after diagnosis. Conclusions: This study provides some important information about the commonly observed treatments and prescription patterns during the COVID-19 pandemic in Yemen during May- July of 2020. The study reflects the influence of global trends in medication prescription even in resource-limited countries.

Association of prescription opioid use on mortality and hospital length of stay in the intensive care unit.

OBJECTIVE: Several studies show that chronic opioid dependence leads to higher in-hospital mortality, increased risk of hospital readmissions, and worse outcomes in trauma cases. However, the association of outpatient prescription opioid use on morbidity and mortality has not been adequately evaluated in a critical care setting. The purpose of this study was to determine if there is an association between chronic opioid use and mortality after an ICU admission. DESIGN: A single-center, longitudinal retrospective cohort study of all Intensive Care Unit (ICU) patients admitted to a tertiary-care academic medical center from 2001 to 2012 using the MIMIC-III database. SETTING: Medical Information Mart for Intensive Care III database based in the United States. PATIENTS: Adult patients 18 years and older were included. Exclusion criteria comprised of patients who expired during their hospital stay or presented with overdose; patients with cancer, anoxic brain injury, non-prescription opioid use; or if an accurate medication reconciliation was unable to be obtained. Patients prescribed chronic opioids were compared with those who had not been prescribed opioids in the outpatient setting. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The final sample included a total of 22,385 patients, with 2,621 (11.7%) in the opioid group and 19,764 (88.3%) in the control group. After proceeding with bivariate analyses, statistically significant and clinically relevant differences were identified between opioid and non-opioid users in sex, length of hospital stay, and comorbidities. Opioid use was associated with increased mortality in both the 30-day and 1-year windows with a respective odds ratios of 1.81 (95% CI, 1.63-2.01; p<0.001) and 1.88 (95% CI, 1.77-1.99; p<0.001), respectively. CONCLUSIONS: Chronic opioid usage was associated with increased hospital length of stay and increased mortality at both 30 days and 1 year after ICU admission. Knowledge of this will help providers make better choices in patient care and have a more informed risk-benefits discussion when prescribing opioids for chronic usage.

A pilot study of an anti-endotoxin Ig-enriched bovine colostrum to prevent experimental sepsis.

Despite the dramatic increase in antimicrobial resistance, there is a dearth of antibiotics in development and few pharmaceutical companies working in the field. Further, any new antibiotics are likely to have a short shelf life. Ab-based interventions offer alternatives that are not likely to be circumvented by the widely prevalent antibiotic resistance genes. Bovine colostrum (BC)-the first milk after parturition, rich in nutrients and immune components-promotes gut integrity and modulates the gut microbiome. We developed a hyperimmune BC (HBC) enriched in Abs to a highly conserved LOS core region of Gram-negative bacteria by immunizing pregnant cows with a vaccine comprised of detoxified LOS from Escherichia coli O111 Rc (J5) mutant non-covalently complexed to group B meningococcal outer membrane protein (J5dLOS/OMP). This vaccine generated robust levels of anti-J5 LOS Ab in the colostrum. When given orally to neutropenic rats challenged orally with Pseudomonas aeruginosa, administration of HBC improved survival compared to non-immune rats, while both BC preparations improved survival compared to PBS controls. Elevated circulating endotoxin levels correlated with mortality. HBC and to a lesser extent non-immune BC reduced bacterial burden from the liver, lung, and spleen. We conclude that HBC and to a lesser extent BC may be effective supplements that improve outcome from lethal gut-derived disseminated infection and may reduce transmission of Gram-negative bacilli from the gastrointestinal tract.

COVID-19 pandemic in Yemen: A questionnaire based survey, what do we know?

INTRODUCTION: Coronavirus infectious disease 2019 (COVID-19) is currently one of the most important public health crises affecting the global human population. It continues to spread widely, as the world still lacks specific treatments and a vaccine for the virus. The scenario of COVID-19 in Yemen seems obscure due to the lack of adequate data, therefore, we developed an electronic questionnaire and distributed it online among Yemeni people. The aim of this study was to understand the COVID-19 epidemiological situation in Yemen better since there is currently limited published data and limited availability of COVID-19 testing. METHODOLOGY: A 34-question web-based survey was distributed on social media outlets targeting people in Yemen. Data aggregation, analysis, and visualization were performed using Tableau and Microsoft Excel. RESULTS: 2,341 individuals reported symptoms concerning for COVID-19 infection, with 25.4% reporting a chronic medical condition. Diabetes, hypertension, asthma, and immune deficiency were associated with increased severity of the disease, while obesity, cardiovascular disease, kidney disease, and liver disease were not. Only 37 individuals (1.6%) had a confirmatory COVID-19 PCR test. The presence of high fever, dyspnea, chest pain, and dysphagia were symptoms that tended to be correlated to worse clinical outcomes. CONCLUSIONS: This study provides some important information about the early overspread of COVID-19 within the Yemeni community in May, June, and July of 2020. It shows that online questionnaires may help in collecting data about pandemics in resource-limited countries where testing availability is limited.

Whatever happened to the Shwartzman phenomenon?

Ninety years ago, Gregory Shwartzman first reported an unusual discovery following the intradermal injection of sterile culture filtrates from principally Gram-negative strains from bacteria into normal rabbits. If this priming dose was followed in 24 h by a second intravenous challenge (the provocative dose) from same culture filtrate, dermal necrosis at the first injection site would regularly occur. This peculiar, but highly reproducible, event fascinated the microbiologists, hematologists, and immunologists of the time, who set out to determine the mechanisms that underlie the pathogenesis of this reaction. The speed of this reaction seemed to rule out an adaptive, humoral, immune response as its cause. Histopathologic material from within the necrotic center revealed fibrinoid, thrombo-hemorrhagic necrosis within small arterioles and capillaries in the micro-circulation. These pathologic features bore a striking resemblance to a more generalized coagulopathic phenomenon following two repeated endotoxin injections described 4 yr earlier by Sanarelli. This reaction came to be known as the generalized Shwartzman phenomenon, while the dermal reaction was named the localized or dermal Shwartzman reaction. A third category was later added, called the single organ or mono-visceral form of the Shwartzman phenomenon. The occasional occurrence of typical pathological features of the generalized Shwartzman reaction limited to a single organ is notable in many well-known clinical events (e.g., hyper-acute kidney transplant rejection, fulminant hepatic necrosis, or adrenal apoplexy in Waterhouse-Fredrickson syndrome). We will briefly review the history and the significant insights gained from understanding this phenomenon regarding the circuitry and control mechanisms responsible for disseminated intravascular coagulation, the vasculopathy and the immunopathy of sepsis.

One-year mortality after recovery from critical illness: A retrospective cohort study.

RATIONALE: Factors associated with one-year mortality after recovery from critical illness are not well understood. Clinicians generally lack information regarding post-hospital discharge outcomes of patients from the intensive care unit, which may be important when counseling patients and families. OBJECTIVE: We sought to determine which factors among patients who survived for at least 30 days post-ICU admission are associated with one-year mortality. METHODS: Single-center, longitudinal retrospective cohort study of all ICU patients admitted to a tertiary-care academic medical center from 2001-2012 who survived ≥30 days from ICU admission. Cox's proportional hazards model was used to identify the variables that are associated with one-year mortality. The primary outcome was one-year mortality. RESULTS: 32,420 patients met the inclusion criteria and were included in the study. Among patients who survived to ≥30 days, 28,583 (88.2%) survived for greater than one year, whereas 3,837 (11.8%) did not. Variables associated with decreased one-year survival include: increased age, malignancy, number of hospital admissions within the prior year, duration of mechanical ventilation and vasoactive agent use, sepsis, history of congestive heart failure, end-stage renal disease, cirrhosis, chronic obstructive pulmonary disease, and the need for renal replacement therapy. Numerous effect modifications between these factors were found. CONCLUSION: Among survivors of critical illness, a significant number survive less than one year. More research is needed to help clinicians accurately identify those patients who, despite surviving their acute illness, are likely to suffer one-year mortality, and thereby to improve the quality of the decisions and care that impact this outcome.

Severe Pneumonia Caused by Legionella pneumophila: Differential Diagnosis and Therapeutic Considerations.

Severe legionella pneumonia poses a diagnostic challenge and requires early intervention. Legionnaire's disease can have several presenting signs, symptoms, and laboratory abnormalities that suggest that Legionella pneumophila is the pathogen, but none of these are sufficient to distinguish L pneumophila pneumonia from other respiratory pathogens. L pneumophila is primarily an intracellular pathogen and needs treatment with antibiotics that efficiently enter the intracellular space.

Management of Atrial Fibrillation with Rapid Ventricular Response in the Intensive Care Unit: A Secondary Analysis of Electronic Health Record Data.

PURPOSE: Atrial fibrillation with rapid ventricular response (RVR) is common during critical illness. In this study, we explore the comparative effectiveness of three commonly used drugs (metoprolol, diltiazem, and amiodarone) in the management of atrial fibrillation with RVR in the intensive care unit (ICU). METHODS: Data pertaining to the first ICU admission were extracted from the Medical Information Mart for Intensive Care III database. Patients who received one of the above pharmacologic agents while their heart rate was > 110 bpm and had atrial fibrillation documented in the clinical chart were included. Propensity score weighting using a generalized boosted model was used to compare medication failure rates (second agent prior to termination of RVR). Secondary outcomes included time to control, control within 4 h, and mortality. RESULTS: One thousand six hundred forty-six patients were included: 736 received metoprolol, 292 received diltiazem, and 618 received amiodarone. Compared with those who received metoprolol, failure rates were higher amongst those who received amiodarone (OR 1.39, 95% CI 1.03-1.87, P = 0.03) and there was a trend towards increased failure rates in patients who received diltiazem (OR 1.35, CI 0.89-2.07, P = 0.16). Amongst patients who received a single agent, patients who received diltiazem were less likely to be controlled at 4-h than those who received metoprolol (OR 0.64, CI 0.43-097, P = 0.03). Initial agent was not associated with in-hospital mortality. CONCLUSIONS: In this study, metoprolol was the most commonly used agent for atrial fibrillation with RVR. Metoprolol had a lower failure rate than amiodarone and was superior to diltiazem in achieving rate control at 4 h.

False alarm reduction in critical care.

High false alarm rates in the ICU decrease quality of care by slowing staff response times while increasing patient delirium through noise pollution. The 2015 PhysioNet/Computing in Cardiology Challenge provides a set of 1250 multi-parameter ICU data segments associated with critical arrhythmia alarms, and challenges the general research community to address the issue of false alarm suppression using all available signals. Each data segment was 5 minutes long (for real time analysis), ending at the time of the alarm. For retrospective analysis, we provided a further 30 seconds of data after the alarm was triggered. A total of 750 data segments were made available for training and 500 were held back for testing. Each alarm was reviewed by expert annotators, at least two of whom agreed that the alarm was either true or false. Challenge participants were invited to submit a complete, working algorithm to distinguish true from false alarms, and received a score based on their program's performance on the hidden test set. This score was based on the percentage of alarms correct, but with a penalty that weights the suppression of true alarms five times more heavily than acceptance of false alarms. We provided three example entries based on well-known, open source signal processing algorithms, to serve as a basis for comparison and as a starting point for participants to develop their own code. A total of 38 teams submitted a total of 215 entries in this year's Challenge. This editorial reviews the background issues for this challenge, the design of the challenge itself, the key achievements, and the follow-up research generated as a result of the Challenge, published in the concurrent special issue of Physiological Measurement. Additionally we make some recommendations for future changes in the field of patient monitoring as a result of the Challenge.

PHARMACOLOGICAL SIRT1 ACTIVATION IMPROVES MORTALITY AND MARKEDLY ALTERS TRANSCRIPTIONAL PROFILES THAT ACCOMPANY EXPERIMENTAL SEPSIS.

The sirtuin family consists of seven NAD+-dependent enzymes affecting a broad array of regulatory protein networks by primarily catalyzing the deacetylation of key lysine residues in regulatory proteins. The enzymatic activity of SIRT1 can be enhanced by small molecule activators known as SIRT1 activator compounds (STACs). We tested the therapeutic potential of the STAC SRT3025 in two preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis and intratracheal installation of Streptococcus pneumoniae to induce severe bacterial pneumonia. SRT3025 provided significant survival benefits over vehicle control in both the peritonitis and pneumococcal pneumonia models when administered with appropriate antimicrobial agents. The survival benefit of SRT3025 in the CLP model was absent in SIRT1 knockout showing the SIRT1 dependency of SRT3025's effects. SRT3025 administration promoted bacterial clearance and significantly reduced inflammatory cytokines from the lungs of animals challenged with S. pneumoniae. SRT3025 treatment was also accompanied by striking changes in the transcription profiles in multiple inflammatory and metabolic pathways in liver, spleen, small bowel, and lung tissue. Remarkably, these organ-specific changes in the transcriptome analyses were similar following CLP or pneumococcal challenge despite different sets of pathogens at disparate sites of infection. Pharmacologic activation of SIRT1 modulates the innate host response and could represent a novel treatment strategy for severe infection.

Risk factors for prolonged H1N1 influenza among hospitalized patients.

In our study, 50% of 42 hospitalized patients with 2009 H1N1 pandemic influenza experienced symptoms longer than 1 week. Older age and delay in oseltamivir initiation were associated with prolonged illness. Patients with pneumonia and fever ≥7 days were more likely to have polymerase chain reaction-positive nasopharyngeal swabs beyond 1 week.