The Effect of Fluid Resuscitation Timing in Early Sepsis Resuscitation.

PURPOSE: The dose and timing of early fluid resuscitation in sepsis remains a debated topic. The objective of this study is to evaluate the effect of fluid timing in early sepsis management on mortality and other clinical outcomes. METHODS: Single-center, retrospective cohort study of emergency-department-treated adults (>18 years, n = 1032) presenting with severe sepsis or septic shock. Logistic regression evaluating the impact of 30 mL/kg crystalloids timing and mortality-versus-time plot controlling for mortality in emergency department sepsis score, lactate, antibiotic timing, obesity, sex, systemic inflammatory response syndrome criteria, hypotension, and heart and renal failures. This study is a subanalysis of a previously published investigation. RESULTS: Mortality was 17.1% (n = 176) overall and 20.4% (n = 133 of 653) among those in septic shock. 30 mL/kg was given to 16.9%, 32.2%, 16.2%, 14.5%, and 20.3% of patients within ≤1, 1 ≤ 3, 3 ≤ 6, 6 ≤ 24, and not reached within 24 h, respectively. A 24-h plot of adjusted mortality versus time did not reach significance, but within the first 12 h, the linear function showed a per-hour mortality increase (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.02-1.67) which peaks around 5h, although the quadratic function does not reach significance (P = .09). When compared to patients receiving 30 mL/kg within 1 h, increased mortality was observed when not reached within 24 h (OR 2.69, 95% CI 1.37-5.37) but no difference when receiving this volume between 1 and 3 (OR 1.11, 95% CI 0.62-2.01), 3 and 6 (OR 1.83, 95% CI 0.97-3.52), or 6 and 24 h (OR 1.51, 95% CI 0.75-3.06). Receiving 30 mL/kg between 1 and 3 versus <1 h increased the incidence of delayed hypotension (OR 1.83, 95% CI 1.23-2.72) but did not impact need for intubation, intensive care unit admission, or vasopressors. CONCLUSIONS: We observed weak evidence that supports that earlier is better for survival when reaching fluid goals of 30 mL/kg, but benefits may wane at later time points. These findings should be viewed as hypothesis generating.

Evaluation and Predictors of Fluid Resuscitation in Patients With Severe Sepsis and Septic Shock.

OBJECTIVES: Rapid fluid resuscitation has become standard in sepsis care, despite "low-quality" evidence and absence of guidelines for populations "at risk" for volume overload. Our objectives include as follows: 1) identify predictors of reaching a 30 mL/kg crystalloid bolus within 3 hours of sepsis onset (30by3); 2) assess the impact of 30by3 and fluid dosing on clinical outcomes; 3) examine differences in perceived "at-risk" volume-sensitive populations, including end-stage renal disease, heart failure, obesity, advanced age, or with documentation of volume "overload" by bedside examination. DESIGN: Retrospective cohort study. All outcome analyses controlled for sex, end-stage renal disease, heart failure, sepsis severity (severe sepsis vs septic shock), obesity, Mortality in Emergency Department Sepsis score, and time to antibiotics. SETTING: Urban, tertiary care center between January 1, 2014, and May 31, 2017. PATIENTS: Emergency Department treated adults (age ≥18 yr; n = 1,032) with severe sepsis or septic shock. INTERVENTIONS: Administration of IV fluids by bolus. MEASUREMENTS AND MAIN RESULTS: In total, 509 patients received 30by3 (49.3%). Overall mortality was 17.1% (n = 176), with 20.4% mortality in the shock group. Patients who were elderly (odds ratio, 0.62; 95% CI, 0.46-0.83), male (odds ratio, 0.66; CI, 0.49-0.87), obese (odds ratio, 0.18; CI, 0.13-0.25), or with end-stage renal disease (odds ratio, 0.23; CI, 0.13-0.40), heart failure (odds ratio, 0.42; CI, 0.29-0.60), or documented volume "overload" (odds ratio, 0.30; CI, 0.20-0.45) were less likely to achieve 30by3. Failure to meet 30by3 had increased odds of mortality (odds ratio, 1.52; CI, 1.03-2.24), delayed hypotension (odds ratio, 1.42; CI, 1.02-1.99), and increased ICU stay (~2 d) (ß = 2.0; CI, 0.5-3.6), without differential effects for "at-risk" groups. Higher fluid volumes administered by 3 hours correlated with decreased mortality, with a plateau effect between 35 and 45 mL/kg (p < 0.05). CONCLUSIONS: Failure to reach 30by3 was associated with increased odds of in-hospital mortality, irrespective of comorbidities. Predictors of inadequate resuscitation can be identified, potentially leading to interventions to improve survival. These findings are retrospective and require future validation.

Association of Country-wide Coronavirus Mortality with Demographics, Testing, Lockdowns, and Public Wearing of Masks.

We studied sources of variation between countries in per-capita mortality from COVID-19 (caused by the SARS-CoV-2 virus). Potential predictors of per-capita coronavirus-related mortality in 200 countries by May 9, 2020 were examined, including age, gender, obesity prevalence, temperature, urbanization, smoking, duration of the outbreak, lockdowns, viral testing, contact-tracing policies, and public mask-wearing norms and policies. Multivariable linear regression analysis was performed. In univariate analysis, the prevalence of smoking, per-capita gross domestic product, urbanization, and colder average country temperature were positively associated with coronavirus-related mortality. In a multivariable analysis of 196 countries, the duration of the outbreak in the country, and the proportion of the population aged 60 years or older were positively associated with per-capita mortality, whereas duration of mask-wearing by the public was negatively associated with mortality (all P < 0.001). Obesity and less stringent international travel restrictions were independently associated with mortality in a model which controlled for testing policy. Viral testing policies and levels were not associated with mortality. Internal lockdown was associated with a nonsignificant 2.4% reduction in mortality each week (P = 0.83). The association of contact-tracing policy with mortality was not statistically significant (P = 0.06). In countries with cultural norms or government policies supporting public mask-wearing, per-capita coronavirus mortality increased on average by just 16.2% each week, as compared with 61.9% each week in remaining countries. Societal norms and government policies supporting the wearing of masks by the public, as well as international travel controls, are independently associated with lower per-capita mortality from COVID-19.

Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites.

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.

Novel Synthetic Polyamines Have Potent Antimalarial Activities in vitro and in vivo by Decreasing Intracellular Spermidine and Spermine Concentrations.

Twenty-two compounds belonging to several classes of polyamine analogs have been examined for their ability to inhibit the growth of the human malaria parasite Plasmodium falciparum in vitro and in vivo. Four lead compounds from the thiourea sub-series and one compound from the urea-based analogs were found to be potent inhibitors of both chloroquine-resistant (Dd2) and chloroquine-sensitive (3D7) strains of Plasmodium with IC50 values ranging from 150 to 460 nM. In addition, the compound RHW, N1,N7-bis (3-(cyclohexylmethylamino) propyl) heptane-1,7-diamine tetrabromide was found to inhibit Dd2 with an IC50 of 200 nM. When RHW was administered to P. yoelii-infected mice at 35 mg/kg for 4 days, it significantly reduced parasitemia. RHW was also assayed in combination with the ornithine decarboxylase inhibitor difluoromethylornithine, and the two drugs were found not to have synergistic antimalarial activity. Furthermore, these inhibitors led to decreased cellular spermidine and spermine levels in P. falciparum, suggesting that they exert their antimalarial activities by inhibition of spermidine synthase.

CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii.

Toxoplasma gondii, an Apicomplexan parasite, causes significant morbidity and mortality, including severe disease in immunocompromised hosts and devastating congenital disease, with no effective treatment for the bradyzoite stage. To address this, we used the Tropical Disease Research database, crystallography, molecular modeling, and antisense to identify and characterize a range of potential therapeutic targets for toxoplasmosis. Phosphoglycerate mutase II (PGMII), nucleoside diphosphate kinase (NDK), ribulose phosphate 3-epimerase (RPE), ribose-5-phosphate isomerase (RPI), and ornithine aminotransferase (OAT) were structurally characterized. Crystallography revealed insights into the overall structure, protein oligomeric states and molecular details of active sites important for ligand recognition. Literature and molecular modeling suggested potential inhibitors and druggability. The targets were further studied with vivoPMO to interrupt enzyme synthesis, identifying the targets as potentially important to parasitic replication and, therefore, of therapeutic interest. Targeted vivoPMO resulted in statistically significant perturbation of parasite replication without concomitant host cell toxicity, consistent with a previous CRISPR/Cas9 screen showing PGM, RPE, and RPI contribute to parasite fitness. PGM, RPE, and RPI have the greatest promise for affecting replication in tachyzoites. These targets are shared between other medically important parasites and may have wider therapeutic potential.