Sepsis endotypes identified by host gene expression across global cohorts

Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

Fecal microbiota transplantation stimulates type 2 and tolerogenic immune responses in a mouse model

Editorial

Famotidine Use Is Not Associated With 30-day Mortality: A Coarsened Exact Match Study in 7158 Hospitalized Patients With Coronavirus Disease 2019 From a Large Healthcare System

SUMMARYMost authorities believe that the greatest need for blood substitutes is in patients with unanticipated acute blood loss, and trauma is the most likely scenario. The blood substitutes reaching advanced clinical trials today are red blood cell (RBC) substitutes, derived from hemoglobin. The hemoglobin‐based oxygen carriers (HBOCs) tested currently in FDA Phase III clinical trials are polymerized hemoglobin solutions. In the USA, the standard approach to restoring oxygen delivery in hemorrhagic shock has been crystalloid administration to expand intravascular volume, followed by stored RBCs for critical anemia. Allogeneic RBCs, however, may have adverse immunoinflammatory effects that increase the risk of postinjury multiple organ failure (MOF). Phase II clinical trials, as well as in vitro and in vivo work, suggest that resuscitation with a HBOC – in lieu of stored RBCs – attenuates the systemic inflammatory response invoked in the pathogenesis of MOF. Specifically, a HBOC has been shown to obviate stored RBC provoked neutrophil (PMN) priming, endothelial activation, and systemic release of interleukins 6,8, and 10. Based on this background and work by others, we have initiated a multicenter prehospital trial in which severely injured patients with major blood loss (SBP < 90 mm Hg) are randomized to initial field resuscitation with crystalloid versus HBOC. During the hospital phase the control group is further resuscitated with stored RBCs, whereas the study group receives HBOC (up to 6 units) in the first 12 hours. The primary study endpoint is 30‐day mortality, and secondary endpoints include reduction in allogeneic RBCs, hemoglobin levels < 5 g/dL, uncrossmatched RBCs, and MOF. The potential efficacy of HBOCs expands beyond the temporary replacement for stored RBCs. Hemoglobin solutions might ultimately prove superior in delivering oxygen to ischemic or injured tissue. The current generation of HBOCs can be lifesaving for acute blood loss today, but the next generation might be biochemically tailored for specific clinical indications.

Tranexamic acid (TXA) administration is recommended in severely injured trauma patients. We examined TXA administration, admission fibrinolysis phenotypes, and clinical outcomes following traumatic injury and hypothesized that TXA was associated with increased multiple organ failure (MOF). Two-year, single-center, retrospective investigation. Inclusion criteria were age ≥ 18 years, Injury Severity Score (ISS) >16, admitted from scene of injury, thromboelastography within 30 min of arrival. Fibrinolysis was evaluated by lysis at 30 min (LY30) and fibrinolysis phenotypes were defined as: Shutdown: LY30 ≤ 0.8%, Physiologic: LY30 0.81-2.9%, Hyperfibrinolysis: LY30 ≥ 3.0%. Primary outcomes were 28-day mortality and MOF. The association of TXA with mortality and MOF was assessed among the entire study population and in each of the fibrinolysis phenotypes. Four hundred twenty patients: 144/420 Shutdown (34.2%), 96/420 Physiologic (22.9%), and 180/410 Hyperfibrinolysis (42.9%). There was no difference in 28-day mortality by TXA administration among the entire study population (P = 0.52). However, there was a significant increase in MOF in patients who received TXA (11/46, 23.9% vs 16/374, 4.3%; P < 0.001). TXA was associated MOF (OR: 3.2, 95% CI 1.2-8.9), after adjusting for confounding variables. There was no difference in MOF in patients who received TXA in the Physiologic (1/5, 20.0% vs 7/91, 7.7%; P = 0.33) group. There was a significant increase in MOF among patients who received TXA in the Shutdown (3/11, 27.3% vs 5/133, 3.8%; P = 0.001) and Hyperfibrinolysis (7/30, 23.3% vs 5/150, 3.3%; P = 0.001) groups. Administration of TXA following traumatic injury was associated with MOF in the fibrinolysis shutdown and hyperfibrinolysis phenotypes and warrants continued evaluation.

A comparison of colorectal cancer in Nigerian and North American patients: Is the cancer biology different?

IntroductionThe predisposition, infection, response and organ dysfunction (PIRO) staging system was designed as a stratification tool to deal with the inherent heterogeneity of septic patients. The present study was conducted to assess the performance of PIRO in predicting multiple organ dysfunction (MOD), intensive care unit (ICU) admission, and 28-day mortality in septic patients in the emergency department (ED), and to compare this scoring system with the Mortality in Emergency Department Sepsis (MEDS) and Acute Physiology and Chronic Health Evaluation (APACHE II) scores.MethodsConsecutive septic patients (n = 680) admitted to the ED of Beijing Chao-Yang Hospital were enrolled. PIRO, MEDS, and APACHE II scores were calculated for each patient on ED arrival. Organ function was reassessed within 3 days of enrollment. All patients were followed up for 28 days. Outcome criteria were the development of MOD within 3 days, ICU admission or death within 28 days after enrollment. The predictive ability of the four components of PIRO was analyzed separately. Receiver operating characteristic (ROC) curve and logistic regression analysis were used to assess the prognostic and risk stratification value of the scoring systems.ResultsOrgan dysfunction independently predicted ICU admission, MOD, and 28-day mortality, with areas under the ROC curve (AUC) of 0.888, 0.851, and 0.816, respectively. The predictive value of predisposition, infection, and response was weaker than that of organ dysfunction. A negative correlation was found between the response component and MOD, as well as mortality. PIRO, MEDS, and APACHE II scores significantly differed between patients who did and did not meet the outcome criteria (P < 0.001). PIRO and APACHE II independently predicted ICU admission and MOD, but MEDS did not. All three systems were independent predictors of 28-day mortality with similar AUC values. The AUC of PIRO was 0.889 for ICU admission, 0.817 for MOD, and 0.744 for 28-day mortality. The AUCs of PIRO were significantly greater than those of APACHE II and MEDS (P < 0.05) in predicting ICU admission and MOD.ConclusionsThe study indicates that PIRO is helpful for risk stratification and prognostic determinations in septic patients in the ED.

Radiation therapy quality assurance in clinical trials – Global harmonisation group

Outcome prediction by serum calprotectin in patients with COVID-19 in the emergency department

In some groups of polytrauma patients, particularly those with chest injuries, head injuries, and those with mangled extremities, early total care of major bone fractures may be potentially harmful. Delaying all orthopaedic surgery, however, is also not always the best approach. In these situations, damage control orthopaedics, which emphasizes the stabilization and control of the injury rather than repair will add little additional physiologic insult to the patient and is a treatment option that should be considered.

Propelled by the advent of novel oncogenic pathway-targeting drugs and increasing regulatory expectations to fulfil proof of mechanism endpoints in clinical trials, there is a critical need to reliably evaluate target inhibition by investigational drugs in biologically relevant compartments. However, the ability to monitor modulation of labile oncogenic pathway biomarkers in global hematomalignancy clinical trials is complicated by varying technical expertise at clinical sites, when specimen stability considerations do not permit analysis at a central specialty laboratory. To address this critical gap, we developed a novel preservation system, designated NovaPerm3 (NP3), that enables stabilization of phosphoprotein based biomarker specimens in a single step, requires less than 20 minutes, and can be implemented in routine clinical trial settings. Stabilized specimens can be frozen and analyzed even after 90 days in a specialized laboratory. Using the NP3 preservation system, we systematically developed and validated a flow cytometry assay that not only enables reliable identification of neoplastic plasma cells but also allows for quantitation of phosphoprotein biomarkers in the tumor cells of interest present in both the peripheral blood (PB) and bone marrow (BM). We will describe a) modulation of phosphorylation levels of the S6 ribosomal protein (pS6RP) by a novel anticancer agent in multiple myeloma patients b) qualitative concordance between NP3-flow cytometry and western blot results from multiple drug treated leukemia cell lines c) sensitive detection of neoplastic plasma cells up to 1% of the total white cells and d) specimen (pS6RP) stabilization over a 90 day period. In conclusion, our novel preservation method and clinical trial laboratory validated flow assay enables reliable quantification of signaling biomarkers in hematomalignancy trials with ease in a specialized central laboratory while reducing the procedural burden for collecting biomarker specimens in global clinical trials. Citation Format: Anil Pahuja, Shyam Sarikonda, Benjamin Lee, Armin Graber, Shabnam Tangri, Naveen Dakappagari. Analytical validation and clinical verification of phosphoprotein biomarker modulation using a novel preservation system-based flow cytometry assay in multiple myeloma clinical trials. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3388. doi:10.1158/1538-7445.AM2015-3388

We sought to investigate potential racial disparities in early outcomes of young individuals with stroke in an international multicenter study. We evaluated consecutive patients with first-ever acute stroke aged 18-45 years from prospective databases involving 12 tertiary-care stroke centers in North America (n = 2), Europe (n = 6), and Asia (n = 4). Demographics, vascular risk factors, stroke subtypes, pre-stroke functional status, stroke severity, blood pressure parameters, and serum glucose at hospital admission were documented. The outcome events of interest were 30-day mortality and 30-day favorable functional outcome (FFO) defined as modified-Rankin Scale score of 0-1. A total of 1,134 young adults (mean age 37.4 ± 7.0 years; 58.8 % men; 48.6 % Whites, 23.9 % Blacks, and 27.5 % Asians; median baseline National Institutes of Health Stroke Scale score 6 points, interquartile range 2-13) were included in the analyses. The 30-day stroke mortality and FFO rates differed (p < 0.001) across races. After adjusting for potential confounders, race was independently associated with 30-day mortality (p = 0.026) and 30-day FFO (p = 0.035). Blacks had a fourfold higher odds of 30-day stroke mortality in comparison to Asians (OR 4.00; 95 % CI 1.38-11.59; p = 0.011). Whites also had an increased likelihood of 30-day stroke mortality in comparison to Asians (OR 3.59; 95 % CI 1.28-10.03; p = 0.015). Blacks had a lower odds of 30-day FFO in comparison to Whites (OR 0.57; 95 % CI 0.35-0.91; p = 0.018). Racial disparities in early outcomes following first-ever stroke in young individuals appear to be independent of other known outcome predictor variables. Whites appear to have higher likelihood of 30-day FFO and Asians have lower odds of 30-day stroke mortality.

BackgroundGiven the limited collaborative international studies that evaluated COVID-19 in patients with cancer in comparison to patients without cancer, we aimed to determine the independent risk factors associated with increased 30-day mortality and the impact of novel treatment modalities in a large group of cancer and non-cancer patients with COVID-19 from multiple countries.MethodsWe retrospectively collected de-identified data on cancer and non-cancer patients diagnosed with COVID-19 between January and November 2020, at 16 centers in Asia, Australia, Europe, North America, and South America. A logistic regression model was used to identify independent predictors of all-cause mortality within 30 days after COVID-19 diagnosis.ResultsOf the total 4015 COVID-19 confirmed patients entered, we analyzed 3966 patients, 1115 cancer and 2851 non-cancer patients. Cancer patients were older than non-cancer patients (median age, 61 vs 50 years; p< 0.0001); more likely to be pancytopenic , had pulmonary disorders, hypertension, diabetes mellitus. In addition, they were more likely to present with higher inflammatory biomarkers (D-dimer, ferritin and procalcitonin), but were less likely to present with clinical symptoms. By multivariable logistic regression analysis, cancer was an independent risk factor for 30-day mortality (OR 1.46; 95% CI 1.03 to 2.07; p=0.035). Older age (≥65 years) was the strongest predictor of 30-day mortality in all patients (OR 4.55; 95% CI 3.34 to 6.20; p< 0.0001). Remdesivir was the only therapeutic agent independently associated with decreased 30-day mortality (OR 0.58; CI 0.39-0.88; p=0.009). Among patients on low-flow oxygen at admission, patients who received remdesivir had a lower 30-day mortality rate than those who were on high flow oxygen (5.9% vs 17.6%; p=0.03). Patients transfused with convalescent plasma within 1 day of diagnosis had a lower 30-day mortality rate than those transfused later (1% vs 7%, p=0.04).ConclusionCancer is an independent risk factor for increased 30-day all-cause mortality from COVID-19. Remdesivir, particularly in patients receiving low-flow oxygen, can reduce 30-day all-cause mortality, as well as convalescent plasma given early after COVID-19 diagnosis.DisclosuresRoy F. Chemaly, MD, MPH, FACP, FIDSA, AiCuris (Grant/Research Support)Ansun Biopharma (Consultant, Grant/Research Support)Chimerix (Consultant, Grant/Research Support)Clinigen (Consultant)Genentech (Consultant, Grant/Research Support)Janssen (Consultant, Grant/Research Support)Karius (Grant/Research Support)Merck (Consultant, Grant/Research Support)Molecular Partners (Consultant, Advisor or Review Panel member)Novartis (Grant/Research Support)Oxford Immunotec (Consultant, Grant/Research Support)Partner Therapeutics (Consultant)Pulmotec (Consultant, Grant/Research Support)Shire/Takeda (Consultant, Grant/Research Support)Viracor (Grant/Research Support)Xenex (Grant/Research Support) Fareed Khawaja, MBBS, Eurofins Viracor (Research Grant or Support) Monica Slavin, MBBS,MD, F2G (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Pfizer (Advisor or Review Panel member) Dimitrios P. Kontoyiannis, MD, Astellas (Consultant)Cidara Therapeutics (Advisor or Review Panel member)Gilead Sciences (Consultant, Grant/Research Support, Other Financial or Material Support, Honoraria)

Ebola vaccine trials back on track