De Novo Human Angiotensin-Converting Enzyme 2 Decoy NL-CVX1 Protects Mice From Severe Disease After Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

The emergence of novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need to investigate alternative approaches to prevent infection and treat patients with coronavirus disease 2019. Here, we report the preclinical efficacy of NL-CVX1, a de novo decoy that blocks virus entry into cells by binding with nanomolar affinity and high specificity to the receptor-binding domain of the SARS-CoV-2 spike protein. Using a transgenic mouse model of SARS-CoV-2 infection, we showed that a single prophylactic intranasal dose of NL-CVX1 conferred complete protection from severe disease following SARS-CoV-2 infection. Multiple therapeutic administrations of NL-CVX1 also protected mice from succumbing to infection. Finally, we showed that infected mice treated with NL-CVX1 developed both anti-SARS-CoV-2 antibodies and memory T cells and were protected against reinfection a month after treatment. Overall, these observations suggest NL-CVX1 is a promising therapeutic candidate for preventing and treating severe SARS-CoV-2 infections.

Morbidity, mortality, and long-term consequences associated with diarrhoea from Cryptosporidium infection in children younger than 5 years: a meta-analyses study.

BACKGROUND: The protozoan Cryptosporidium is a leading cause of diarrhoea morbidity and mortality in children younger than 5 years. However, the true global burden of Cryptosporidium infection in children younger than 5 years might have been underestimated in previous quantifications because it only took account of the acute effects of diarrhoea. We aimed to demonstrate whether there is a causal relation between Cryptosporidium and childhood growth and, if so, to quantify the associated additional burden. METHODS: The Global Burden of Diseases, Injuries, and Risk Factors study (GBD) 2016 was a systematic and scientific effort to quantify the morbidity and mortality associated with more than 300 causes of death and disability, including diarrhoea caused by Cryptosporidium infection. We supplemented estimates on the burden of Cryptosporidium in GBD 2016 with findings from a systematic review of published and unpublished cohort studies and a meta-analysis of the effect of childhood diarrhoea caused by Cryptosporidium infection on physical growth. FINDINGS: In 2016, Cryptosporidium infection was the fifth leading diarrhoeal aetiology in children younger than 5 years, and acute infection caused more than 48 000 deaths (95% uncertainty interval [UI] 24 600-81 900) and more than 4·2 million disability-adjusted life-years lost (95% UI 2·2 million-7·2 million). We identified seven data sources from the scientific literature and six individual-level data sources describing the relation between Cryptosporidium and childhood growth. Each episode of diarrhoea caused by Cryptosporidium infection was associated with a decrease in height-for-age Z score (0·049, 95% CI 0·014-0·080), weight-for-age Z score (0·095, 0·055-0·134), and weight-for-height Z score (0·126, 0·057-0·194). We estimated that diarrhoea from Cryptosporidium infection caused an additional 7·85 million disability-adjusted life-years (95% UI 5·42 million-10·11 million) after we accounted for its effect on growth faltering-153% more than that estimated from acute effects alone. INTERPRETATION: Our findings show that the substantial short-term burden of diarrhoea from Cryptosporidium infection on childhood growth and wellbeing is an underestimate of the true burden. Interventions designed to prevent and effectively treat infection in children younger than 5 years will have enormous public health and social development impacts. FUNDING: The Bill & Melinda Gates Foundation.

Morbidity and mortality due to shigella and enterotoxigenic Escherichia coli diarrhoea: the Global Burden of Disease Study 1990-2016.

BACKGROUND: Shigella and enterotoxigenic Escherichia coli (ETEC) are bacterial pathogens that are frequently associated with diarrhoeal disease, and are a significant cause of mortality and morbidity worldwide. The Global Burden of Diseases, Injuries, and Risk Factors study 2016 (GBD 2016) is a systematic, scientific effort to quantify the morbidity and mortality due to over 300 causes of death and disability. We aimed to analyse the global burden of shigella and ETEC diarrhoea according to age, sex, geography, and year from 1990 to 2016. METHODS: We modelled shigella and ETEC-related mortality using a Bayesian hierarchical modelling platform that evaluates a wide range of covariates and model types on the basis of vital registration and verbal autopsy data. We used a compartmental meta-regression tool to model the incidence of shigella and ETEC, which enforces an association between incidence, prevalence, and remission on the basis of scientific literature, population representative surveys, and health-care data. We calculated 95% uncertainty intervals (UIs) for the point estimates. FINDINGS: Shigella was the second leading cause of diarrhoeal mortality in 2016 among all ages, accounting for 212 438 deaths (95% UI 136 979-326 913) and about 13·2% (9·2-17·4) of all diarrhoea deaths. Shigella was responsible for 63 713 deaths (41 191-93 611) among children younger than 5 years and was frequently associated with diarrhoea across all adult age groups, increasing in elderly people, with broad geographical distribution. ETEC was the eighth leading cause of diarrhoea mortality in 2016 among all age groups, accounting for 51 186 deaths (26 757-83 064) and about 3·2% (1·8-4·7) of diarrhoea deaths. ETEC was responsible for about 4·2% (2·2-6·8) of diarrhoea deaths in children younger than 5 years. INTERPRETATION: The health burden of bacterial diarrhoeal pathogens is difficult to estimate. Despite existing prevention and treatment options, they remain a major cause of morbidity and mortality globally. Additional emphasis by public health officials is needed on a reduction in disease due to shigella and ETEC to reduce disease burden. FUNDING: Bill & Melinda Gates Foundation.

Pediatric cryptosporidiosis: An evaluation of health care and societal costs in Peru, Bangladesh and Kenya.

Cryptosporidium is a leading cause of pediatric diarrhea in resource-limited settings; yet, few studies report the health care costs or societal impacts of this protozoan parasite. Our study examined direct and indirect costs associated with symptomatic cryptosporidiosis in infants younger than 12 months in Kenya, Peru and Bangladesh. Inputs to the economic burden model, such as disease incidence, population size, health care seeking behaviour, hospital costs, travel costs, were extracted from peer-reviewed literature, government documents, and internationally validated statistical tools for each country. Indirect losses (i.e. caregiver income loss, mortality, and growth faltering) were also estimated. Our findings suggest that direct treatment costs per symptomatic cryptosporidiosis episode were highest in Kenya ($59.01), followed by Peru ($23.32), and Bangladesh ($7.62). The total annual economic impacts for the 0-11 month cohorts were highest in Peru ($41.5M; range $0.88-$599.3M), followed by Kenya ($37.4M; range $1.6-$804.5M) and Bangladesh ($9.6M, range $0.28-$91.5M). For all scenarios, indirect societal costs far outweighed direct treatment costs. These results highlight the critical need for innovative improvements to current prevention, diagnostic and treatment strategies available in resource poor settings, as well as the need for solutions that span multiple disciplines including food and water safety, sanitation and livestock production.

Outcomes of osteomyelitis among patients treated with outpatient parenteral antimicrobial therapy.

PURPOSE: To examine the effects of diabetes, vascular disease, age, and antimicrobial therapy on clinical outcomes, including amputation rates, in patients with osteomyelitis treated in the outpatient setting. METHODS: We performed a retrospective chart review of patients treated with intravenous antimicrobial therapy for osteomyelitis at an outpatient infectious diseases practice. All patients were followed for at least 6 months. RESULTS: Four hundred and fifty-four patients qualified for inclusion, with follow-up information available for up to 10 years. One hundred and thirty-nine patients (31%) had recurrences and 27 (6%) had amputations. Of the recurrences, 108 (78%) occurred within 6 months and 132 (95%) within 1 year. In univariate analyses, peripheral vascular disease, diabetes, and the combination were all associated with the risk of recurrence; age (>70 years) was not. For osteomyelitis due to Staphylococcus aureus, the relative risk of recurrence, using a Cox regression model, was 0.8 for ceftriaxone (95% confidence interval [CI]: 0.4 to 1.5; P = 0.53), 1.1 for cefazolin (95% CI: 0.5 to 2.2; P = 0.80), and 2.5 for vancomycin (95% CI: 1.1 to 5.6; P = 0.04), as compared with the use of a penicillinase-resistant penicillin. CONCLUSION: Diabetes and peripheral vascular disease are important factors in determining the prognosis of patients with osteomyelitis, but age is not. Almost all recurrences of osteomyelitis occur within 1 year. Recurrence rates with osteomyelitis associated with S. aureus appear to be higher with the use of vancomycin, whereas ceftriaxone and cefazolin appear to be similar to penicillinase-resistant penicillins.

Risk factors and treatment outcomes in osteomyelitis.

Outcome indicators of recurrence and amputation were used to evaluate risk factors and treatment choices in 454 patients with osteomyelitis who completed outpatient parenteral antimicrobial therapy (OPAT). Three hundred and fifteen (69.4%) were apparently cured at the time outcomes were measured and 139 (30.6%) had a recurrence. Of the recurrences, 56% occurred within 3 months, 78% within 6 months and 95% within 1 year. Both the initial pathogen and the choice of antibiotic had an effect on the risk of treatment failure. Osteomyelitis caused by Pseudomonas aeruginosa was associated with more than a two-fold increase in recurrence (P = 0.005) compared with infection caused by Staphylococcus aureus. There was a positive correlation between P. aeruginosa and amputation. With S. aureus infections, the risk of recurrence was more than twice as great with vancomycin therapy as opposed to treatment with beta-lactams (P = 0.03). Treatment with ceftriaxone was as effective as the penicillinase-resistant penicillins and cefazolin.

Lack of hepatotoxicity associated with nonnucleoside reverse transcriptase inhibitors.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs), particularly nevirapine, have been associated with hepatotoxicity. We performed a retrospective study to determine the incidence of NNRTI hepatotoxicity in a group of HIV-infected patients from a New York City practice. These patients are predominantly homosexual white males. We also analyzed the effect of coinfection with hepatitis B (HBV) or hepatitis C (HCV) virus. In total, 272 patients received NNRTIS: 40 (15%) received delavirdine, 91 (33%) received efavirenz, and 141 (52%) received nevirapine. Of the patients with known hepatitis status, 18 of 190 (9%) were coinfected with HBV, and 24 of 205 were coinfected (12%) with HCV. The overall rate of grade 3 to 4 elevations in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) was 3 of 272 (1.1%) and did not differ significantly among the three NNRTIs. HBV or HCV was not associated with a significant increase in AST or ALT elevations. We conclude that NNRTIs are relatively free from hepatotoxicity in this population, despite the presence of coinfection with HBV or HCV.