Effect of Immediate Administration of Antibiotics in Patients With Sepsis in Tertiary Care:A Systematic Review and Meta-analysis

Purpose The goal of this review was to synthesize existing evidence regarding outcomes (mortality) for patients who present to the emergency department, are administered antibiotics immediately (within 1 hour) or later (>1 hour), and are diagnosed with sepsis. Methods A search of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL, using the MeSH descriptors “sepsis,” “systemic inflammatory response syndrome,” “mortality,” “emergency,” and “antibiotics,” was performed to identify studies reporting time to antibiotic administration and mortality outcome in patients with sepsis. The included studies (published in English between 1990 and 2016) listed patient mortality based on time to antibiotic administration. Studies were evaluated for methodologic quality, and data were extracted by using a data extraction form tailored to this study. From an initial pool of 582 potentially relevant studies, 11 studies met our inclusion criteria, 10 of which had quantitative data for meta-analysis. Three different models (a random effects model, a bias-adjusted quality-effects [synthetic bias] model, and an inverse variance heterogeneity model) were used to perform the meta-analysis. Findings The pooled results suggest a significant 33% reduction in mortality odds for immediate (within 1 hour) compared with later (>1 hour) antibiotic administration (OR, 0.67 [95% CI, 0.59–0.75]) in patients with sepsis. Implications Immediate antibiotic administration (<1 hour) seemed to reduce patient mortality. There was some minor negative asymmetry suggesting that the evidence may be biased toward the direction of effect. Nevertheless, this study provides strong evidence for early, comprehensive, sepsis management in the emergency department

Nomenclature for renal replacement therapy and blood purification techniques in critically ill patients: practical applications

This article reports the conclusions of the second part of a consensus expert conference on the nomenclature of renal replacement therapy (RRT) techniques currently utilized to manage acute kidney injury and other organ dysfunction syndromes in critically ill patients. A multidisciplinary approach was taken to achieve harmonization of definitions, components, techniques, and operations of the extracorporeal therapies. The article describes the RRT techniques in detail with the relevant technology, procedures, and phases of treatment and key aspects of volume management/fluid balance in critically ill patients. In addition, the article describes recent developments in other extracorporeal therapies, including therapeutic plasma exchange, multiple organ support therapy, liver support, lung support, and blood purification in sepsis. This is a consensus report on nomenclature harmonization in extracorporeal blood purification therapies, such as hemofiltration, plasma exchange, multiple organ support therapies, and blood purification in sepsis

Clinical Impact of Ceftriaxone Resistance in Escherichia coli Bloodstream Infections: A Multicenter Prospective Cohort Study

BACKGROUND: Ceftriaxone-resistant (CRO-R) Escherichia coli bloodstream infections (BSIs) are common. METHODS: This is a prospective cohort of patients with E coli BSI at 14 United States hospitals between November 2020 and April 2021. For each patient with a CRO-R E coli BSI enrolled, the next consecutive patient with a ceftriaxone-susceptible (CRO-S) E coli BSI was included. Primary outcome was desirability of outcome ranking (DOOR) at day 30, with 50% probability of worse outcomes in the CRO-R group as the null hypothesis. Inverse probability weighting (IPW) was used to reduce confounding. RESULTS: Notable differences between patients infected with CRO-R and CRO-S E coli BSI included the proportion with Pitt bacteremia score ≥4 (23% vs 15%, P = .079) and the median time to active antibiotic therapy (12 hours [interquartile range {IQR}, 1-35 hours] vs 1 hour [IQR, 0-6 hours]; P \u3c .001). Unadjusted DOOR analyses indicated a 58% probability (95% confidence interval [CI], 52%-63%) for a worse clinical outcome in CRO-R versus CRO-S BSI. In the IPW-adjusted cohort, no difference was observed (54% [95% CI, 47%-61%]). Secondary outcomes included unadjusted and adjusted differences in the proportion of 30-day mortality between CRO-R and CRO-S BSIs (-5.3% [95% CI, -10.3% to -.4%] and -1.8 [95% CI, -6.7% to 3.2%], respectively), postculture median length of stay (8 days [IQR, 5-13 days] vs 6 days [IQR, 4-9 days]; P \u3c .001), and incident admission to a long-term care facility (22% vs 12%, P = .045). CONCLUSIONS: Patients with CRO-R E coli BSI generally have poorer outcomes compared to patients infected with CRO-S E coli BSI, even after adjusting for important confounders

Sex differences in DNA methylation and expression in zebrafish brain: a test of an extended ‘male sex drive’ hypothesis

The sex drive hypothesis predicts that stronger selection on male traits has resulted in masculinization of the genome. Here we test whether such masculinizing effects can be detected at the level of the transcriptome and methylome in the adult zebrafish brain. Although methylation is globally similar, we identified 914 specific differentially methylated CpGs (DMCs) between males and females (435 were hypermethylated and 479 were hypomethylated in males compared to females). These DMCs were prevalent in gene body, intergenic regions and CpG island shores. We also discovered 15 distinct CpG clusters with striking sex-specific DNA methylation differences. In contrast, at transcriptome level, more female-biased genes than male-biased genes were expressed, giving little support for the male sex drive hypothesis. Our study provides genome-wide methylome and transcriptome assessment and sheds light on sex-specific epigenetic patterns and in zebrafish for the first time

Characterisation of the Cell Line HC-AFW1 Derived from a Pediatric Hepatocellular Carcinoma

Current treatment of paediatric hepatocellular carcinoma (HCC) is often inefficient due to advanced disease at diagnosis and resistance to common drugs. The aim of this study was to generate a cell line derived from a paediatric HCC in order to expand research in this field. We established the HC-AFW1 cell line from a liver neoplasm of a 4-year-old boy through culturing of primary tumor specimens. The cell line has been stable for over one year of culturing and has a doubling time of 40 h. The tumour cells have an epithelial histology and express HCC-associated proteins such as Alpha-fetoprotein (AFP), Glypican 3, E-cadherin, CD10, CD326, HepPar1 and Vimentin. Forty-nine amino acids in exon 3 of β-Catenin that involve the phosphorylation sites of GSK3 were absent and β-Catenin is detectable in the cell nuclei. Cytogenetic analysis revealed large anomalies in the chromosomal map. Several alterations of gene copy numbers were detected by genome-wide SNP array. Among the different drugs tested, cisplatin and irinotecan showed effective inhibition of tumour cell growth in a proliferation assay at concentrations below 5 µg/ml. Subcutaneous xenotransplantation of HC-AFW1 cells into NOD/SCID mice resulted in fast growing dedifferentiated tumours with high levels of serum AFP. Histological analyses of the primary tumour and xenografts included national and international expert pathological review. Consensus reading characterised the primary tumour and the HC-AFW1-derived tumours as HCC. HC-AFW1 is the first cell line derived from a paediatric HCC without a background of viral hepatitis or cirrhosis and represents a valuable tool for investigating the biology of and therapeutic strategies for childhood HCC

Hospital Readmissions in Patients With Carbapenem-Resistant <span class="italic">Klebsiella pneumoniae</span>

BACKGROUND: Various transmission routes contribute to spread of carbapenem-resistant Klebsiella pneumoniae (CRKP) in hospitalized patients. Patients with readmissions during which CRKP is again isolated ("CRKP readmission") potentially contribute to transmission of CRKP. OBJECTIVE: To evaluate CRKP readmissions in the Consortium on Resistance against Carbapenems in K. pneumoniae (CRaCKLe). DESIGN: Cohort study from December 24, 2011, through July 1, 2013. SETTING: Multicenter consortium of acute care hospitals in the Great Lakes region. PATIENTS: All patients who were discharged alive during the study period were included. Each patient was included only once at the time of the first CRKP-positive culture. METHODS: All readmissions within 90 days of discharge from the index hospitalization during which CRKP was again found were analyzed. Risk factors for CRKP readmission were evaluated in multivariable models. RESULTS: Fifty-six (20%) of 287 patients who were discharged alive had a CRKP readmission. History of malignancy was associated with CRKP readmission (adjusted odds ratio [adjusted OR], 3.00 [95% CI, 1.32-6.65], P<.01). During the index hospitalization, 160 patients (56%) received antibiotic treatment against CRKP; the choice of regimen was associated with CRKP readmission (P=.02). Receipt of tigecycline-based therapy (adjusted OR, 5.13 [95% CI, 1.72-17.44], using aminoglycoside-based therapy as a reference in those treated with anti-CRKP antibiotics) was associated with CRKP readmission. CONCLUSION: Hospitalized patients with CRKP-specifically those with a history of malignancy-are at high risk of readmission with recurrent CRKP infection or colonization. Treatment during the index hospitalization with a tigecycline-based regimen increases this risk

The BH3 mimetic ABT-737 increases treatment efficiency of paclitaxel against hepatoblastoma

<p>Abstract</p> <p>Background</p> <p>The primary goal of current chemotherapy in hepatoblastoma (HB) is reduction of tumour volume and vitality to enable complete surgical resection and reduce risk of recurrence or metastatic disease. Drug resistance remains a major challenge for HB treatment. In some malignancies inhibition of anti-apoptotic pathways using small BH3 mimetic molecules like ABT-737 shows synergistic effects in combination with cystotoxic agents in vitro. Now we analysed toxicology and synergistic effects of this approach in HB cells and HB xenografts.</p> <p>Methods</p> <p>Viability was monitored in HB cells (HUH6 and HepT1) and fibroblasts treated with paclitaxel, ABT-737 and a combination of both in a MTT assay. HUH6 xenotransplants in NOD/LtSz-scid IL2Rγnull mice (NSG) were treated accordingly. Tumour volume and body weight were monitored. Xenografted tumours were analysed by histology and immunohistochemistry (Ki-67 and TUNEL assay).</p> <p>Results</p> <p>ABT-737 reduced viability in HUH6 and HepT1 cells cultures at concentrations above 1 μM and also enhanced the cytotoxic effect of paclitaxel when used in combination. Thereby paclitaxel could be reduced tenfold to achieve similar reduction of viability of tumour cells. In contrast no toxicity in fibroblasts was observed at the same regiments. Subcutaneous HB (HUH6) treated with paclitaxel (12 mg/kg body weight, n = 7) led to delayed tumour growth in the beginning of the experiment. However, tumour volume was similar to controls (n = 5) at day 25. Combination treatment with paclitaxel and ABT-737 (100 mg/kg, n = 8) revealed significantly 10 fold lower relative tumour volumes compared to control and paclitaxel groups. Paclitaxel dependent toxicity was observed in this mice strain.</p> <p>Conclusions</p> <p>Our results demonstrate enhancement of chemotherapy by using modulators of apoptosis. Further analyses should include improved pharmacological formulations of paclitaxel and BH3 mimetics in order to reduce toxicological effects. Sensitising HB to apoptosis may also render resistant HB susceptible to established chemotherapy regimens.</p

Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): a prospective cohort study

BACKGROUND: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA. METHODS: We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day the index culture was collected. We compared outcomes of patients with CRPA infections by infection type and across geographic regions and performed an inverse probability weighted analysis to assess the association between carbapenemase production and 30-day mortality. FINDINGS: We enrolled 972 patients (USA n=527, China n=171, south and central America n=127, Middle East n=91, Australia and Singapore n=56), of whom 581 (60%) had CRPA infections. 30-day mortality differed by infection type (bloodstream 21 [30%] of 69, respiratory 69 [19%] of 358, wound nine [14%] of 66, urine six [7%] of 88; p=0·0012) and geographical region (Middle East 15 [29%] of 52, south and central America 20 [27%] of 73, USA 60 [19%] of 308, Australia and Singapore three [11%] of 28, China seven [6%] of 120; p=0·0002). Prevalence of carbapenemase genes among CRPA isolates also varied by region (south and central America 88 [69%] of 127, Australia and Singapore 32 [57%] of 56, China 54 [32%] of 171, Middle East 27 [30%] of 91, USA ten [2%] of 527; p\u3c0·0001). KPC-2 (n=103 [49%]) and VIM-2 (n=75 [36%]) were the most common carbapenemases in 211 carbapenemase-producing isolates. After excluding USA patients, because few US isolates had carbapenemases, patients with carbapenemase-producing CRPA infections had higher 30-day mortality than those with non-carbapenemase-producing CRPA infections in both unadjusted (26 [22%] of 120 vs 19 [12%] of 153; difference 9%, 95% CI 3-16) and adjusted (difference 7%, 95% CI 1-14) analyses. INTERPRETATION: The emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms. FUNDING: National Institutes of Health

Epidemiología mundial y resultados clínicos de Pseudomonas aeruginosa resistente a carbapenemes y carbapenemasas asociadas (POP): un estudio prospectivo de cohortes

Antecedentes: La Pseudomonas aeruginosa resistente a los carbapenemes (CRPA) es una amenaza mundial, pero la distribución y la importancia clínica de las carbapenemasas no están claras. El objetivo de este estudio fue definir las características y los resultados de las infecciones por CRPA, así como la frecuencia global y el impacto clínico de las carbapenemasas albergadas por CRPA. Métodos: Llevamos a cabo un estudio de cohortes observacional y prospectivo de CRPA aislados de cultivos de torrente sanguíneo, respiratorio, orina o heridas de pacientes en 44 hospitales (10 países) entre el 1 de diciembre de 2018 y el 30 de noviembre de 2019. Los datos clínicos se extrajeron de los registros de salud y los aislados de CRPA se secuenciaron en todo el genoma. El resultado primario fue la mortalidad a 30 días a partir del día en que se recolectó el cultivo índice. Se compararon los resultados de los pacientes con infecciones por CRPA por tipo de infección y entre regiones geográficas y se realizó un análisis ponderado de probabilidad inversa para evaluar la asociación entre la producción de carbapenemasas y la mortalidad a 30 días. Resultados: Se incluyeron 972 pacientes (EE.UU. n=527, China n=171, América del Sur y Central n=127, Oriente Medio n=91, Australia y Singapur n=56), de los cuales 581 (60%) tenían infecciones por CRPA. La mortalidad a los 30 días difería según el tipo de infección (torrente sanguíneo 21 [30%] de 69, respiratoria 69 [19%] de 358, herida nueve [14%] de 66, orina seis [7%] de 88; p=0-0012) y la región geográfica (Oriente Medio 15 [29%] de 52, América del Sur y Central 20 [27%] de 73, EE.UU. 60 [19%] de 308, Australia y Singapur tres [11%] de 28, China siete [6%] de 120; p=0-0002). La prevalencia de genes carbapenemasa entre los aislados CRPA también varió según la región (América del Sur y Central 88 [69%] de 127, Australia y Singapur 32 [57%] de 56, China 54 [32%] de 171, Oriente Medio 27 [30%] de 91, EE.UU. diez [2%] de 527; p<0-0001). KPC-2 (n=103 [49%]) y VIM-2 (n=75 [36%]) fueron las carbapenemasas más comunes en 211 aislados productores de carbapenemasas. Después de excluir a los pacientes de EE.UU., porque pocos aislados de EE.UU. tenían carbapenemasas, los pacientes con infecciones por CRPA productoras de carbapenemasas tuvieron una mayor mortalidad a los 30 días que aquellos con infecciones por CRPA no productoras de carbapenemasas, tanto en los análisis no ajustados (26 [22%] de 120 frente a 19 [12%] de 153; diferencia 9%, IC 95% 3-16) como ajustados (diferencia 7%, IC 95% 1-14). Interpretación: La aparición de diferentes carbapenemasas entre los aislados de CRPA en diferentes regiones geográficas y el aumento de la mortalidad asociada a las infecciones por CRPA productores de carbapenemasas ponen de manifiesto los retos terapéuticos que plantean estos organismos. Financiación: Institutos Nacionales de Salud.Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA. Methods: We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day the index culture was collected. We compared outcomes of patients with CRPA infections by infection type and across geographic regions and performed an inverse probability weighted analysis to assess the association between carbapenemase production and 30-day mortality. Findings: We enrolled 972 patients (USA n=527, China n=171, south and central America n=127, Middle East n=91, Australia and Singapore n=56), of whom 581 (60%) had CRPA infections. 30-day mortality differed by infection type (bloodstream 21 [30%] of 69, respiratory 69 [19%] of 358, wound nine [14%] of 66, urine six [7%] of 88; p=0·0012) and geographical region (Middle East 15 [29%] of 52, south and central America 20 [27%] of 73, USA 60 [19%] of 308, Australia and Singapore three [11%] of 28, China seven [6%] of 120; p=0·0002). Prevalence of carbapenemase genes among CRPA isolates also varied by region (south and central America 88 [69%] of 127, Australia and Singapore 32 [57%] of 56, China 54 [32%] of 171, Middle East 27 [30%] of 91, USA ten [2%] of 527; p<0·0001). KPC-2 (n=103 [49%]) and VIM-2 (n=75 [36%]) were the most common carbapenemases in 211 carbapenemase-producing isolates. After excluding USA patients, because few US isolates had carbapenemases, patients with carbapenemase-producing CRPA infections had higher 30-day mortality than those with non-carbapenemase-producing CRPA infections in both unadjusted (26 [22%] of 120 vs 19 [12%] of 153; difference 9%, 95% CI 3–16) and adjusted (difference 7%, 95% CI 1–14) analyses. Interpretation: The emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms. Funding: National Institutes of Health

In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability.</p> <p>Methods</p> <p>6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA.</p> <p>Results</p> <p>MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm³+/-243 mm³) with MRI (mean 918 mm³+/-193 mm³) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm²+/-22.8 mm²versus 32.6 mm²+/-22.6 mm²(histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm³+/-56.7 mm³after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals.</p> <p>Conclusions</p> <p>This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer.</p