Piplartine-Inspired 3,4,5-Trimethoxycinnamates: Trypanocidal, Mechanism of Action, and In Silico Evaluation.

Chagas disease (CD) is one of the main neglected tropical diseases that promote relevant socioeconomic impacts in several countries. The therapeutic options for the treatment of CD are limited, and parasite resistance has been reported. Piplartine is a phenylpropanoid imide that has diverse biological activities, including trypanocidal action. Thus, the objective of the present work was to prepare a collection of thirteen esters analogous to piplartine (1-13) and evaluate their trypanocidal activity against Trypanosoma cruzi. Of the tested analogues, compound 11 ((E)-furan-2-ylmethyl 3-(3,4,5-trimethoxyphenyl)acrylate) showed good activity with IC50 values = 28.21 ± 5.34 µM and 47.02 ± 8.70 µM, against the epimastigote and trypomastigote forms, respectively. In addition, it showed a high rate of selectivity to the parasite. The trypanocidal mechanism of action occurs through the induction of oxidative stress and mitochondrial damage. In addition, scanning electron microscopy showed the formation of pores and leakage of cytoplasmic content. Molecular docking indicated that 11 probably produces a trypanocidal effect through a multi-target mechanism, including affinity with proteins CRK1, MPK13, GSK3B, AKR, UCE-1, and UCE-2, which are important for the survival of the parasite. Therefore, the results suggest chemical characteristics that can serve for the development of new trypanocidal prototypes for researching drugs against Chagas disease.

Optical switching a photon-avalanche-like mechanism in NdAl3(BO3)4 particles excited at 1064 nm by an auxiliary beam at 808 nm.

In recent years, an unconventional excitation of trivalent neodymium ions (N d 3+) at 1064 nm, not resonant with ground-state transitions, has been investigated with the unprecedented demonstration of a photon-avalanche-like (PA-like) mechanism, in which the temperature increase plays a fundamental role. As a proof-of-concept, N d A l 3(B O 3)4 particles were used. A consequence of the PA-like mechanism is the absorption enhancement of excitation photons providing light emission at a broad range covering the visible and near-infrared spectra. In the first study, the temperature increase was due to intrinsic nonradiative relaxations from the N d 3+ and the PA-like mechanism ensued at a given excitation power threshold (P t h ). Subsequently, an external heating source was used to trigger the PA-like mechanism while keeping the excitation power below P t h at room temperature. Here, we demonstrate the switching on of the PA-like mechanism by an auxiliary beam at 808 nm, which is in resonance with the N d 3+ ground-state transition 4 I 9/2→{4 F 5/2,2 H 9/2}. It comprises the first, to the best of our knowledge, demonstration of an optical switched PA, and the underlying physical mechanism is the additional heating of the particles due to the phonon emissions from the N d 3+ relaxation pathways when exciting at 808 nm. The present results have potential applications in controlled heating and remote temperature sensing.

CLINICAL, MOLECULAR, AND EXOSOMAL MECHANISMS OF CARDIAC AND BRAIN DYSFUNCTION IN SEPSIS.

ABSTRACT: Sepsis is a complex disease resulting from a dysregulated inflammatory response to an infection. Initiation of sepsis occurs from a localized infection that disseminates to the bloodstream placing all organ systems at risk. Septic shock is classically observed to manifest itself as systemic hypotension with hyporesponsiveness to vasopressor agents. Myocardial dysfunction occurs resulting in an inability to perfuse major organ systems throughout the body. Most importantly, the brain is hypoperfused creating an ischemic and inflammatory state resulting in the clinical observation of acute mental status changes and cognitive dysfunction commonly known as sepsis-associated encephalopathy. This short review describes the inflammatory molecular mechanisms of myocardial dysfunction, discusses the evidence of the dual roles of the microglia resulting in blood-brain barrier disruption, and suggests that septic-derived exosomes, endosome-derived lipid bilayer spheroids released from living cells, influence cardiac and neurological cellular function.

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection.

Importance: Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship. Objective: To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI. Design, Setting, and Participants: This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc. Interventions: The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection. Main Outcomes and Measures: Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement. Results: Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection. Conclusions and Relevance: In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.

Accelerated Critical Therapy Now in the Emergency Department Using an Early Intervention Team: The Impact of Early Critical Care Consultation for ICU Boarders.

Evaluate the impact of an emergency department (ED)-based critical care consultation service, hypothesizing early consultation results in shorter hospital length of stay (LOS). DESIGN: Retrospective observational study from February 2018 to 2020. SETTING: An urban academic quaternary referral center. PATIENTS: Adult patients greater than or equal to 18 years admitted to the ICU from the ED. Exclusion criteria included age less than 18 years, do not resuscitate/do not intubate documented prior to arrival, advanced directives outlining limitations of care, and inability to calculate baseline modified Sequential Organ Failure Assessment (mSOFA) score. INTERVENTIONS: ED-based critical care consultation by an early intervention team (EIT) initiated by the primary emergency medicine physician compared with usual practice. MEASUREMENTS: The primary outcome was hospital LOS, and secondary outcomes were hospital mortality, ICU LOS, ventilator-free days, and change in the mSOFA. MAIN RESULTS: A total 1,764 patients met inclusion criteria, of which 492 (27.9%) were evaluated by EIT. Final analysis, excluding those without baseline mSOFA score, limited to 1,699 patients, 476 in EIT consultation group, and 1,223 in usual care group. Baseline mSOFA scores (±sd) were higher in the EIT consultation group at 3.6 (±2.4) versus 2.6 (±2.0) in the usual care group. After propensity score matching, there was no difference in the primary outcome: EIT consultation group had a median (interquartile range [IQR]) LOS of 7.0 days (4.0-13.0 d) compared with the usual care group median (IQR) LOS of 7.0 days (4.0-13.0 d), p = 0.64. The median (IQR) boarding time was twice as long subjects in the EIT consultation group at 8.0 (5.0-15.0) compared with 4.0 (3.0-7.0) usual care, p < 0.001. CONCLUSIONS: An ED-based critical care consultation model did not impact hospital LOS. This model was used in the ED and the EIT cared for critically ill patients with higher severity of illness and longer ED boarding times.

Intraosseous vascular access using the EZ-IO can be safely maintained in the adult proximal humerus and proximal tibia for up to 48 h: Report of a clinical study.

BACKGROUND: Historically, intraosseous (IO) vascular access devices cleared to market by the US FDA have been restricted to 24-h use. An observational study was conducted to determine the safety of IO access for a period up to 48 h in adult volunteers. METHODS: A 2-arm randomized, stratified, parallel assignment, prospective interventional study was conducted at ICON Early Phase Services in San Antonio, Texas, United States. Study subjects were adult volunteers who were healthy or with a history of mild to moderate renal disease and/or controlled diabetes. Subjects were randomized to receive IO access (Arrow EZ-IO Vascular Access System, Teleflex Medical Incorporated, Morrisville, NC, USA) in the proximal humerus or the proximal tibia and maintain the indwelling catheter for 48 h. Subjects were monitored for the entire dwell time. A culture specimen was drawn from the indwelling catheter tip before removal and insertion site x-rays were taken. RESULTS: 121 subjects were randomized: 79 healthy, 39 with diabetes, and three with diabetes and renal insufficiency. The mean catheter dwell time was 48.0 ± 0.2 h. Overall first attempt success rate was 98.4%. Infusion pain was the most commonly reported adverse event. There were no serious complications or unanticipated adverse events. CONCLUSIONS: This is the first known study examining the safety of IO access over a 48-h dwell time. The study corroborates the literature findings, demonstrates device safety, and provides evidence supporting the extended indication for a dwell time to 48 h in adult patients. IO placement and infusion best practices/guidelines were confirmed or established.

Effects of Compliance With the Early Management Bundle (SEP-1) on Mortality Changes Among Medicare Beneficiaries With Sepsis: A Propensity Score Matched Cohort Study.

BACKGROUND: US hospitals have reported compliance with the SEP-1 quality measure to Medicare since 2015. Finding an association between compliance and outcomes is essential to gauge measure effectiveness. RESEARCH QUESTION: What is the association between compliance with SEP-1 and 30-day mortality among Medicare beneficiaries? STUDY DESIGN AND METHODS: Studying patient-level data reported to Medicare by 3,241 hospitals from October 1, 2015, to March 31, 2017, we used propensity score matching and a hierarchical general linear model (HGLM) to estimate the treatment effects associated with compliance with SEP-1. Compliance was defined as completion of all qualifying SEP-1 elements including lactate measurements, blood culture collection, broad-spectrum antibiotic administration, 30 mL/kg crystalloid fluid administration, application of vasopressors, and patient reassessment. The primary outcome was a change in 30-day mortality. Secondary outcomes included changes in length of stay. RESULTS: We completed two matches to evaluate population-level treatment effects. In standard match, 122,870 patients whose care was compliant were matched with the same number whose care was noncompliant. Compliance was associated with a reduction in 30-day mortality (21.81% vs 27.48%, respectively), yielding an absolute risk reduction (ARR) of 5.67% (95% CI, 5.33-6.00; P < .001). In stringent match, 107,016 patients whose care was compliant were matched with the same number whose care was noncompliant. Compliance was associated with a reduction in 30-day mortality (22.22% vs 26.28%, respectively), yielding an ARR of 4.06% (95% CI, 3.70-4.41; P < .001). At the subject level, our HGLM found compliance associated with lower 30-day risk-adjusted mortality (adjusted conditional OR, 0.829; 95% CI, 0.812-0.846; P < .001). Multiple elements correlated with lower mortality. Median length of stay was shorter among cases whose care was compliant (5 vs 6 days; interquartile range, 3-9 vs 4-10, respectively; P < .001). INTERPRETATION: Compliance with SEP-1 was associated with lower 30-day mortality. Rendering SEP-1 compliant care may reduce the incidence of avoidable deaths.

Comparing the Diagnostic Accuracy of Clinician Judgment to a Novel Host Response Diagnostic for Acute Respiratory Illness.

BACKGROUND: Difficulty discriminating bacterial from viral infections drives antibacterial misuse. Host gene expression tests discriminate bacterial and viral etiologies, but their clinical utility has not been evaluated. METHODS: Host gene expression and procalcitonin levels were measured in 582 emergency department participants with suspected infection. We also recorded clinician diagnosis and clinician-recommended treatment. These 4 diagnostic strategies were compared with clinical adjudication as the reference. To estimate the clinical impact of host gene expression, we calculated the change in overall Net Benefit (∆NB; the difference in Net Benefit comparing 1 diagnostic strategy with a reference) across a range of prevalence estimates while factoring in the clinical significance of false-positive and -negative errors. RESULTS: Gene expression correctly classified bacterial, viral, or noninfectious illness in 74.1% of subjects, similar to the other strategies. Clinical diagnosis and clinician-recommended treatment revealed a bias toward overdiagnosis of bacterial infection resulting in high sensitivity (92.6% and 94.5%, respectively) but poor specificity (67.2% and 58.8%, respectively), resulting in a 33.3% rate of inappropriate antibacterial use. Gene expression offered a more balanced sensitivity (79.0%) and specificity (80.7%), which corresponded to a statistically significant improvement in average weighted accuracy (79.9% vs 71.5% for procalcitonin and 76.3% for clinician-recommended treatment; P<.0001 for both). Consequently, host gene expression had greater Net Benefit in diagnosing bacterial infection than clinician-recommended treatment (∆NB=6.4%) and procalcitonin (∆NB=17.4%). CONCLUSIONS: Host gene expression-based tests to distinguish bacterial and viral infection can facilitate appropriate treatment, improving patient outcomes and mitigating the antibacterial resistance crisis.

Data utilisation and factors influencing the performance of the health management information system in Tanzania.

BACKGROUND: Health Management Information System (HMIS) is a set of data regularly collected at health care facilities to meet the needs of statistics on health services. This study aimed to determine the utilisation of HMIS data and factors influencing the health system's performance at the district and primary health care facility levels in Tanzania. METHODS: This cross-sectional study was carried out in 11 districts and involved 115 health care facilities in Tanzania. Data were collected using a semi-structured questionnaire administered to health workers at facility and district levels and documented using an observational checklist. Thematic content analysis approach was used to synthesise and triangulate the responses and observations to extract essential information. RESULTS: A total of 93 healthcare facility workers and 13 district officials were interviewed. About two-thirds (60%) of the facility respondents reported using the HMIS data, while only five out of 13 district respondents (38.5%) reported analysing HMIS data routinely. The HMIS data were mainly used for comparing performance in terms of services coverage (53%), monitoring of disease trends over time (50%), and providing evidence for community health education and promotion programmes (55%). The majority (41.4%) of the facility's personnel had not received any training on data management related to HMIS during the past 12 months prior to the survey. Less than half (42%) of the health facilities had received supervisory visits from the district office 3 months before this assessment. Nine district respondents (69.2%) reported systematically receiving feedback on the quality of their reports monthly and quarterly from higher authorities. Patient load was described to affect staff performance on data collection and management frequently. CONCLUSION: Inadequate analysis and poor data utilisation practices were common in most districts and health facilities in Tanzania. Inadequate human and financial resources, lack of incentives and supervision, and lack of standard operating procedures on data management were the significant challenges affecting the HMIS performance in Tanzania.

Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test.

OBJECTIVES: Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test. DESIGN: Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results. SETTING: Four U.S. emergency departments. PATIENTS: Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis. INTERVENTIONS: Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes. MEASUREMENTS AND MAIN RESULTS: Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance. CONCLUSIONS: The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use.

Trends, patterns and cause-specific neonatal mortality in Tanzania: a hospital-based retrospective survey.

BACKGROUND: Globally, large numbers of children die shortly after birth and many of them within the first 4 wk of life. This study aimed to determine the trends, patterns and causes of neonatal mortality in hospitals in Tanzania during 2006-2015. METHODS: This retrospective study involved 35 hospitals. Mortality data were extracted from inpatient registers, death registers and International Classification of Diseases-10 report forms. Annual specific hospital-based neonatal mortality rates were calculated and discussed. Two periods of 2006-2010 and 2011-2015 were assessed separately to account for data availability and interventions. RESULTS: A total of 235 689 deaths were recorded and neonatal deaths accounted for 11.3% (n=26 630) of the deaths. The majority of neonatal deaths (87.5%) occurred in the first week of life. Overall hospital-based neonatal mortality rates increased from 2.6 in 2006 to 10.4 deaths per 1000 live births in 2015, with the early neonates contributing 90% to this rate constantly over time. The neonatal mortality rate was 3.7/1000 during 2006-2010 and 10.4/1000 during 2011-2015, both periods indicating a stagnant trend in the years between. The leading causes of early neonatal death were birth asphyxia (22.3%) and respiratory distress (20.8%), while those of late neonatal death were sepsis (29.1%) and respiratory distress (20.0%). CONCLUSION: The majority of neonatal deaths in Tanzania occur among the early newborns and the trend over time indicates a slow improvement. Most neonatal deaths are preventable, hence there are opportunities to reduce mortality rates with improvements in service delivery during the first 7 d and maternal care.

Data quality of the routine health management information system at the primary healthcare facility and district levels in Tanzania.

BACKGROUND: Effective planning for disease prevention and control requires accurate, adequately-analysed, interpreted and communicated data. In recent years, efforts have been put in strengthening health management information systems (HMIS) in Sub-Saharan Africa to improve data accessibility to decision-makers. This study assessed the quality of routine HMIS data at primary healthcare facility (HF) and district levels in Tanzania. METHODS: This cross-sectional study involved reviews of documents, information systems and databases, and collection of primary data from facility-level registers, tally sheets and monthly summary reports. Thirty-four indicators from Outpatient, Inpatient, Antenatal care, Family Planning, Post-natal care, Labour and Delivery, and Provider-Initiated Testing and Counselling service areas were assessed. Indicator records were tracked and compared across the process of data collection, compilation and submission to the district office. Copies of monthly report forms submitted by facilities to the district were also reviewed. The availability and utilization of HMIS tools were assessed, while completeness and data accuracy levels were quantified for each phase of the reporting system. RESULTS: A total of 115 HFs (including hospitals, health centres, dispensaries) in 11 districts were involved. Registers (availability rate = 91.1%; interquartile range (IQR) 66.7-100%) and report forms (86.9%; IQR 62.2-100%) were the most utilized tools. There was a limited use of tally-sheets (77.8%; IQR 35.6-100%). Tools availability at the dispensary was 91.1%, health centre 82.2% and hospital 77.8%, and was low in urban districts. The availability rate at the district level was 65% (IQR 48-75%). Wrongly filled or empty cells in registers and poor adherence to the coding procedures were observed. Reports were highly over-represented in comparison to registers' records, with large differences observed at the HF phase of the reporting system. The OPD and IPD areas indicated the highest levels of mismatch between data source and district office. Indicators with large number of clients, multiple variables, disease categorization, or those linked with dispensing medicine performed poorly. CONCLUSION: There are high variations in the tool utilisation and data accuracy at facility and district levels. The routine HMIS is weak and data at district level inaccurately reflects what is available at the source. These results highlight the need to design tailored and inter-service strategies for improving data quality.

A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Hyaluronidase PH20 Administered Intravenously in Healthy Volunteers.

BACKGROUND: Recombinant human hyaluronidase PH20 (rHuPH20) is used in subcutaneous formulations (eg, RITUXAN HYCELA [rituximab and hyaluronidase human], HERCEPTIN HYLECTA [trastuzumab and hyaluronidase-oysk], PHESGO [pertuzumab/trastuzumab/hyaluronidase-zzxf], and Darzalex FASPRO [daratumumab and hyaluronidase-fihj]) to increase the dispersion and absorption of coadministered therapeutics. Although unlikely, subcutaneous products that include rHuPH20 could be mistaken for the intravenous formulation of the corresponding drugs (eg, RITUXAN [rituximab], HERCEPTIN [trastuzumab], and DARZALEX [daratumumab]). To understand the potential effects of inadvertent intravenous injection of rHuPH20, we investigated the safety profile, pharmacokinetics (PK), and pharmacodynamics (PD) of rHuPH20 administered intravenously. OBJECTIVES: This Phase I, open-label, single-center study in healthy volunteers was designed to assess the safety profile, tolerability, PK, and PD of rHuPH20 administered intravenously. METHODS: Healthy volunteers received 5 mL intravenous infusion of either 10,000 U (n = 12) or 30,000 U (n = 12) rHuPH20 over 5 minutes. Blood samples for PK and PD analysis were obtained at baseline and at various times after initiation of infusion. Adverse events and laboratory parameters were measured to assess the safety profile and tolerability of the intravenous infusion. The PK of rHuPH20 was assessed using both an enzymatic assay and a mass-based immunoassay, and plasma hyaluronan concentrations were measured as a PD marker using an HPLC-MS/MS disaccharide assay. RESULTS: All 24 volunteers (mean age = 36.5 years) completed the study, and no serious adverse events were reported in either treatment group. Overall, 2 adverse events (both Grade 1) were reported; catheter site pain in the 10,000 U group and hypotension in the 30,000 U group. Plasma concentrations of rHuPH20 increased during the 5-minute intravenous infusion (median tmax = 6 minutes from intravenous initiation) followed by a rapid plasma clearance (t1/2 ∼10 minutes from intravenous initiation). Plasma hyaluronan concentrations increased with dose and time (tmax range = 45‒120 minutes from intravenous initiation) and returned to baseline within 1 week of administration. Changes in both PK and PD measurements appeared proportional to dose. CONCLUSIONS: The study demonstrated that intravenous administration of up to 30,000 U rHuPH20 was well tolerated, rapidly cleared from the plasma, and did not appear to be associated with any serious adverse effects at doses used in subcutaneous therapeutic products. (Curr Ther Res Clin Exp. 2020; 81).

Proteomic Profiles of Exosomes of Septic Patients Presenting to the Emergency Department Compared to Healthy Controls.

BACKGROUND: Septic Emergency Department (ED) patients provide a unique opportunity to investigate early sepsis. Recent work focuses on exosomes, nanoparticle-sized lipid vesicles (30-130 nm) that are released into the bloodstream to transfer its contents (RNA, miRNA, DNA, protein) to other cells. Little is known about how early changes related to exosomes may contribute to the dysregulated inflammatory septic response that leads to multi-organ dysfunction. We aimed to evaluate proteomic profiles of plasma derived exosomes obtained from septic ED patients and healthy controls. METHODS: This is a prospective observational pilot study evaluating a plasma proteomic exosome profile at an urban tertiary care hospital ED using a single venipuncture blood draw, collecting 40 cc Ethylenediaminetetraacetic acid (EDTA) blood. MEASUREMENTS: We recruited seven patients in the ED within 6 h of their presentation and five healthy controls. Plasma exosomes were isolated using the Invitrogen Total Exosome Isolation Kit. Exosome proteomic profiles were analyzed using fusion mass spectroscopy and Proteome Discoverer. Principal component analysis (PCA) and differential expression analysis (DEA) for sepsis versus control was performed. RESULTS: PCA of 261 proteins demonstrated septic patients and healthy controls were distributed in two groups. DEA revealed that 62 (23.8%) proteins differed between the exosomes of septic patients and healthy controls, p-value < 0.05. Adjustments using the False Discovery Rate (FDR) showed 23 proteins remained significantly different (FDR < 0.05) between sepsis and controls. Septic patients and controls were classified into two distinct groups by hierarchical clustering using the 62 nominally DE proteins. After adjustment multiple comparisons, three acute phase proteins remained significantly different between patients and controls: Serum amyloid A-1, C-reactive protein and Serum Amyloid A-2. Inflammatory response proteins immunoglobulin heavy constant Δ and Fc-fragment of IgG binding protein were increased. CONCLUSION: Exosome proteomic profiles of septic ED patients differ from their healthy counterparts with regard to acute phase response and inflammation.

A Physiologic Approach to Hemodynamic Monitoring and Optimizing Oxygen Delivery in Shock Resuscitation.

The approach to shock resuscitation focuses on all components of oxygen delivery, including preload, afterload, contractility, hemoglobin, and oxygen saturation. Resuscitation focused solely on preload and fluid responsiveness minimizes other key elements, resulting in suboptimal patient care. This review will provide a physiologic and practical approach for the optimization of oxygen delivery utilizing available hemodynamic monitoring technologies. Venous oxygen saturation (SvO2) and lactate will be discussed as indicators of shock states and endpoints of resuscitation within the framework of resolving oxygen deficit and oxygen debt.

Performance of PCR/Electrospray Ionization-Mass Spectrometry on Whole Blood for Detection of Bloodstream Microorganisms in Patients with Suspected Sepsis.

Blood culture (BC) often fails to detect bloodstream microorganisms in sepsis. However, molecular diagnostics hold great potential. The molecular method PCR/electrospray ionization-mass spectrometry (PCR/ESI-MS) can detect DNA from hundreds of different microorganisms in whole blood. The aim of the present study was to evaluate the performance of this method in a multicenter study including 16 teaching hospitals in the United States (n = 13) and Europe (n = 3). First, on testing of 2,754 contrived whole blood samples, with or without spiked microorganisms, PCR/ESI-MS produced 99.1% true-positive and 97.2% true-negative results. Second, among 1,460 patients with suspected sepsis (sepsis-2 definition), BC and PCR/ESI-MS on whole blood were positive in 14.6% and 25.6% of cases, respectively, with the following result combinations: BC positive and PCR/ESI-MS negative, 4.3%; BC positive and PCR/ESI-MS positive, 10.3%; BC negative and PCR/ESI-MS positive, 15.3%; and BC negative and PCR/ESI-MS negative, 70.1%. Compared with BC, PCR/ESI-MS showed the following sensitivities (coagulase-negative staphylococci not included): Gram-positive bacteria, 58%; Gram-negative bacteria, 78%; and Candida species, 83%. The specificities were >94% for all individual species. Patients who had received prior antimicrobial medications (n = 603) had significantly higher PCR/ESI-MS positivity rates than patients without prior antimicrobial treatment-31% versus 22% (P < 0.0001)-with pronounced differences for Gram-negative bacteria and Candida species. In conclusion, PCR/ESI-MS showed excellent performance on contrived samples. On clinical samples, it showed high specificities, moderately high sensitivities for Gram-negative bacteria and Candida species, and elevated positivity rates during antimicrobial treatment. These promising results encourage further development of molecular diagnostics to be used with whole blood for detection of bloodstream microorganisms in sepsis.

F-Actin is associated with a worsening qSOFA score and intensive care unit admission in emergency department patients at risk for sepsis.

Objective: We previously demonstrated that plasma levels of F-actin and Thymosin Beta 4 differs among patients with septic shock, non-infectious systemic inflammatory syndrome and healthy controls and may serve as biomarkers for the diagnosis of sepsis. The current study aims to determine if these proteins are associated with or predictive of illness severity in patients at risk for sepsis in the Emergency Department (ED).Methods: Prospective, biomarker study enrolling patients (>18 years) who met the Shock Precautions on Triage Sepsis rule placing them at-risk for sepsis.Results: In this study of 203 ED patients, F-actin plasma levels had a linear trend of increase when the quick Sequential Organ Failure Assessment (qSOFA) score increased. F-actin was also increased in patients who were admitted to the Intensive Care Unit (ICU) from the ED, and in those with positive urine cultures. Thymosin Beta 4 was not associated with or predictive of any significant outcome measures.Conclusion: Increased levels of plasma F-actin measured in the ED were associated with incremental illness severity as measured by the qSOFA score and need for ICU admission. F-actin may have utility in risk stratification of undifferentiated patients in the ED presenting with signs and symptoms of sepsis.

Cancer Mortality Patterns in Tanzania: A Retrospective Hospital-Based Study, 2006-2015.

PURPOSE: This retrospective study sought to determine the type, burden, and pattern of cancer deaths in public hospitals in Tanzania from 2006 to 2015. METHODS: This study analyzed data on cancer mortality in 39 hospitals in Tanzania. Data on the age and sex of the deceased and type of cancer were extracted from hospital death registers and report forms. Cancer types were grouped according to the 10th revision of the International Classification of Diseases. Age-standardized mortality rates and cancer mortality patterns were analyzed. A χ2 test was used to examine the association between common cancers and selected covariates. RESULTS: A total of 12,621 cancer-related deaths occurred during the 10-year period, which translates to an age-standardized hospital-based mortality rate of 47.8 per 100,000 population. Overall, the number of deaths was notably higher (56.5%) among individuals in the 15- to 59-year-old age category and disproportionately higher among females than males (P = .0017). Cancers of the cervix, esophagus, and liver were the 3 major causes of death across all study hospitals in Tanzania. Cancers of the cervix, esophagus, and liver were the largest contributors to mortality burden among females. Among males, cancers of the esophagus, liver, and prostate were the leading cause of mortality. CONCLUSION: There is an increasing trend in cancer mortality over recent years in Tanzania, which differs with respect to age, sex, and geographic zones. These findings provide a basis for additional studies to ascertain incidence rates and survival probabilities, and highlight the need to strengthen awareness campaigns for early detection, access to care, and improved diagnostic capabilities.

Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients.

BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality. RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9±23.2 ng per milliliter (117±58 nmol per liter) in the vitamin D group and 11.4±5.6 ng per milliliter (28±14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P = 0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality. CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).