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 was 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.

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) (β = 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.

Globally, congenital toxoplasmosis remains a significant cause of morbidity and mortality, and outbreaks of infection with T. gondii represent a significant, emerging public health burden, especially in the developing world. This parasite is a threat to public health. Disease often is not recognized and is inadequately managed. Herein, we analyze the status of congenital toxoplasmosis in Morocco, Colombia, the United States, and France. We identify the unique challenges faced by each nation in the implementation of optimal approaches to congenital toxoplasmosis as a public health problem. We suggest that developed and developing countries use a multipronged approach, modeling their public health management protocols after those in France. We conclude that education, screening, appropriate treatment, and the development of novel modalities will be required to intervene successfully in caring for individuals with this infection. Gestational screening has been demonstrated to be cost-effective, morbidity-sparing, and life-saving. Recognition of the value and promise of public health interventions to prevent human suffering from this emerging infection will facilitate better patient and societal outcomes.

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We created and tested multi-epitope DNA or protein vaccines with TLR4 ligand emulsion adjuvant (gluco glucopyranosyl lipid adjuvant in a stable emulsion [GLA-SE]) for their ability to protect against Toxoplasma gondii in HLA transgenic mice. Our constructs each included 5 of our best down-selected CD8(+) T cell-eliciting epitopes, a universal CD4(+) helper T lymphocyte epitope (PADRE), and a secretory signal, all arranged for optimal MHC-I presentation. Their capacity to elicit immune and protective responses was studied using immunization of HLA-A*11:01 transgenic mice. These multi-epitope vaccines increased memory CD8(+) T cells that produced IFN-γ and protected mice against parasite burden when challenged with T. gondii. Endocytosis of emulsion-trapped protein and cross presentation of the antigens must account for the immunogenicity of our adjuvanted protein. Thus, our work creates an adjuvanted platform assembly of peptides resulting in cross presentation of CD8(+) T cell-eliciting epitopes in a vaccine that prevents toxoplasmosis

Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc1 complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 30 nM) and cysts (IC50, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc1 complex Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.

BackgroundCongenital toxoplasmosis is a serious but preventable and treatable disease. Gestational screening facilitates early detection and treatment of primary acquisition. Thus, fetal infection can be promptly diagnosed and treated and outcomes can be improved.MethodsWe tested 180 sera with the Toxoplasma ICT IgG-IgM point-of-care (POC) test. Sera were from 116 chronically infected persons (48 serotype II; 14 serotype I-III; 25 serotype I-IIIa; 28 serotype Atypical, haplogroup 12; 1 not typed). These represent strains of parasites infecting mothers of congenitally infected children in the U.S. 51 seronegative samples and 13 samples from recently infected persons known to be IgG/IgM positive within the prior 2.7 months also were tested. Interpretation was confirmed by two blinded observers. A comparison of costs for POC vs. commercial laboratory testing methods was performed.ResultsWe found that this new Toxoplasma ICT IgG-IgM POC test was highly sensitive (100%) and specific (100%) for distinguishing IgG/IgM-positive from negative sera. Use of such reliable POC tests can be cost-saving and benefit patients.ConclusionsOur work demonstrates that the Toxoplasma ICT IgG-IgM test can function reliably as a point-of-care test to diagnose Toxoplasma gondii infection in the U.S. This provides an opportunity to improve maternal-fetal care by using approaches, diagnostic tools, and medicines already available. This infection has serious, lifelong consequences for infected persons and their families. From the present study, it appears a simple, low-cost POC test is now available to help prevent morbidity/disability, decrease cost, and make gestational screening feasible. It also offers new options for improved prenatal care in low- and middle-income countries.

Background. Toxoplasma gondii infection causes substantial morbidity and mortality in the United States, and infects approximately one-third of persons globally. Clinical manifestations vary. Seropositivity is associated with neurologic diseases and malignancies. There are few objective data concerning US incidence and distribution of toxoplasmosis.Methods. Truven Health MarketScan Database and International Classification of Diseases, Ninth Revision (ICD-9) codes, including treatment specific to toxoplasmosis, identified patients with this disease. Spatiotemporal distribution and patterns of disease manifestation were analyzed. Comorbidities between patients and matched controls were compared.Results. Between 2003 and 2012, 9260 patients had ICD-9 codes for toxoplasmosis. This database of patients with ICD-9 codes includes 15% of those in the United States, excluding patients with no or public insurance. Thus, assuming that demographics do not change incidence, the calculated total is 61 700 or 6856 patients per year. Disease was more prevalent in the South. Mean age at diagnosis was 37.5 ± 15.5 years; 2.4% were children aged 0-2 years, likely congenitally infected. Forty-one percent were male, and 73% of women were of reproductive age. Of identified patients, 38% had eye disease and 12% presented with other serious manifestations, including central nervous system and visceral organ damage. Toxoplasmosis was statistically associated with substantial comorbidities, including human immunodeficiency virus, autoimmune diseases, and neurologic diseases.Conclusions. Toxoplasmosis causes morbidity and mortality in the United States. Our analysis of private insurance records missed certain at-risk populations and revealed fewer cases of retinal disease than previously estimated, suggesting undercoding, underreporting, undertreating, or differing demographics of those with eye disease. Mandatory reporting of infection to health departments and gestational screening could improve care and facilitate detection of epidemics and, thereby, public health interventions.