Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used non-human primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. H5N6 HPAIV infection led to high fever in cynomolgus macaques. The lung injury caused by the virus was severe with diffuse alveolar damage and neutrophil infiltration. In addition, an increase in IFN-α showed an inverse correlation with virus titers during the infection process. Oseltamivir was effective for reducing H5N6 HPAIV propagation, and continuous treatment with peramivir reduced virus propagation and severity of symptoms in the early stage. This study also showed the pathologically severe lung injury states in the cynomolgus macaques infected with H5N6 HPAIV, even in those that received early antiviral drug treatments, indicating the need for close monitoring and the need for further studies on the virus pathogenicity and new antiviral therapies.

Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug-resistance to specific anti-influenza drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug nitazoxanide with antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza potentials with 10-fold improvement, compared with nitazoxanide, and were effective against a variety of influenza subtypes including oseltamivir-resistant strains. Notably, the combination using of compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effect against oseltamivir-resistant strain. Mode of action analysis demonstrated that compounds 4a/4d acted at the late phase of viral infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited influenza virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of up-regulated cellular genes that may contribute to the antiviral activities of 4a/4d. Together, our study pointed the optimization direction of nitazoxanide as anti-influenza drug, and discovered two novel-structured candidates 4a/4d with relatively broad-spectrum antiviral potential.

Despite the worldwide re-emergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. We here aim to identify the target of a novel class of CHIKV inhibitors i.e. CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low micromolar range. A CHVB-resistant variant (CHVB^res) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2 and one mutation in nsP3. Reverse genetics studies demonstrated that both nsP1 mutations were necessary and sufficient to achieve ~18-fold resistance, suggesting that CHVB targets viral mRNA capping. Interestingly, CHVB^res was cross-resistant to the previously described CHIKV capping inhibitors from the MADTP series, suggesting they share a similar mechanism of action. In enzymatic assays, CHVB inhibited the methyltransferase and guanylyltransferase activities of alphavirus nsP1 proteins. To conclude, we identified a class of CHIKV inhibitors that targets the viral capping machinery. The potent anti-CHIKV activity makes this chemical scaffold a potential candidate for CHIKV drug development.

Ebola Virus (EBOV) is among the most devastating pathogens causing fatal hemorrhagic fever in humans. The 2013–2016 epidemics resulted in over 11000 deaths, while another outbreak is currently ongoing. Since there is no FDA-approved drug so far to fight EBOV infection, there is an urgent need to focus on drug discovery. Considering the tight correlation between the high EBOV virulence and its ability to suppress the type-I Interferon (IFN-I) system, identifying molecules targeting viral protein VP24, one of the main virulence determinants blocking IFN response, is a promising novel anti-EBOV therapy approach. Hence, in the effort of finding novel EBOV inhibitors, a screening of a small set of flavonoids was performed, showing that Quercetin and Wogonin can suppress the VP24 effect on IFN-I signaling inhibition. The mechanism of action of the most active compound, Quercetin, showing an IC₅₀ value of 7.4 μM, was characterized to significantly restore the IFN-I signaling cascade, blocked by VP24, by directly interfering with the VP24 binding to karyopherin-α and thus restoring P-STAT1 nuclear transport and IFN genes transcription. Quercetin significantly blocked viral infection, specifically targeting EBOV VP24 anti-IFN-I function. Overall, Quercetin is the first identified inhibitor of the EBOV VP24 anti-IFN function, representing a molecule interacting with a viral binding site that is very promising for further drug development aiming to block EBOV infection at the early steps.

Drug repositioning is the only feasible option to address the COVID-19 global challenge immediately. We screened a panel of 48 FDA-approved drugs against SARS-CoV-2 which were pre-selected by an assay of SARS-CoV and identified 24 potential antiviral drug candidates against SARS-CoV-2 infection. Some drug candidates showed very low micromolar IC50s and in particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects.

Earlier genetic and inhibitor studies have shown that epigenetic regulation of gene expression is critical for malaria parasite survival in multiple life stages and a promising target for new anti-malarials. We therefore evaluated the activity of 350 diverse epigenetic inhibitors against multiple stages of Plasmodium falciparum. We observed ≥90% inhibition at 10 μM for 28% of compounds against asexual blood stages and early gametocytes, of which a third retained ≥90% inhibition at 1 μM.

Cyclophilins play a key role in the lifecycle of coronaviruses. Alisporivir (Debio 025) is a non-immunosuppressive analogue of cyclosporin A with potent cyclophilin inhibition properties. Alisporivir reduced SARS-CoV-2 RNA production in a dose-dependent manner in VeroE6 cell line, with an EC₅₀ of 0.46±0.04 μM. Alisporivir inhibited a post-entry step of the SARS-CoV-2 lifecycle. These results justify that a proof-of-concept Phase 2 trial be rapidly conducted with alisporivir in patients with SARS-CoV-2 infection.

BACKGROUND AND OBJECTIVES:

Children with medical complexity (CMC) comprise only 6% of the pediatric population, account for ~40% of pediatric health care spending, and provide an important opportunity for cost saving. Savings in this group can have an important impact on pediatric health care costs. The objective of this study was to assess the impact of a multicenter care management program on spending and use in CMC.

BACKGROUND AND OBJECTIVES:

Children born very preterm (VPT) are at high risk of cognitive impairment that impacts their educational and social opportunities. This study examined the predictive accuracy of assessments at 2, 4, 6, and 9 years in identifying preterm children with cognitive impairment by 12 years.

Ana L. Creo
Dec 1, 2017; 140:e20171486-e20171486
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CNA Staff, Mar 31, 2020 / 06:01 pm (CNA).- Local media in Nicaragua are reporting that despite the nation’s bishops’ conference suspending Mass and prohibiting large gatherings, the mayor of Granada is going ahead with an annual pilgrimage that the bishops had canceled.

For more than 150 years, Catholics in Nicaragua have venerated an image of Jesus del Rescate (Jesus of the Rescue) in Popoyuapa, near the city of Rivas. The image represents the crowning of thorns and the flogging of Christ.

Normally there is an annual pilgrimage to the image, which pilgrims make by wagon and on foot, during the "Week of Sorrows" that marks "the final stretch" of the time of Lent, according to ACI Prensa, CNA’s Spanish language news partner.

However, the bishops have said that this year it will not be possible to carry it out in the traditional way, given the coronavirus (COVID-19) pandemic.

Nevertheless, Julia Mena, mayor of Granada, has organized and funded a group of pilgrims to do the pilgrimage, providing them with food and personal hygiene supplies, according to the Nicaraguan news website Confidencial. The priest at the shrine told Confidencial that he has “no plans to receive the pilgrimage.”

The Nicaraguan Episcopal Conference has not commented publicly on the matter.

Nicaragua has five confirmed cases of COVID-19. The government has not yet decreed any kind of alert or emergency regarding the pandemic, nor has it ordered a suspension of classes, Confidencial reports.

The country’s Ministry of Health has maintained that the internal movements of travelers arriving from countries with outbreaks of coronavirus would not be restricted, La Prensa reports.

President Daniel Ortega has been president of Nicaragua since 2007, and oversaw the abolition of presidential term limits in 2014.

The Church had suggested that elections, which are not scheduled until 2021, be held this year, but Ortega has ruled this out.

Ortega was a leader in the Sandinista National Liberation Front, which had ousted the Somoza dictatorship in 1979 and fought US-backed right-wing counterrevolutionaries during the 1980s. Ortega was also leader of Nicaragua from 1979 to 1990.

Lima, Peru, May 7, 2020 / 06:00 am (CNA).- Two priests in a rural area of Peru aimed to fight the coronavirus pandemic by finding a way to supply oxygen tanks, much needed for medical treatment, to their region.

The recent death of two doctors from coronavirus in Iquitos, Peru, underscored the hard-hit region’s shortage of medical equipment and medications. Both doctors died because of the lack of oxygen to treat them.

The Medical Corps of Hospital III of Iquitos and the Medical College of Peru said in a joint statement last month that there is a shortage of medications in the Loreto region, and its capital Iquitos is "one of the cities hardest hit by the infection."

“We don’t have medications” to treat coronavirus patients and “not enough oxygen tanks, pressure gauges and refilled tanks,” they reported.

One doctor was in intensive care at Loreto Regional Hospital and the other at a hospital under the country’s universal health insurance program, both in Iquitos, the Medical College of Peru said on social media.

Fr. Raymond Portelli, a parish pastor in Iquitos, along with the diocesan administrator of the Apostolic Vicariate of Iquitos, Fr. Miguel Fuertes, decided to start a fundraising campaign to acquire an oxygen plant for the city.

Portelli himself is a doctor caring for COVID-19 patients.

To purchase the machinery, they needed to raise about $118,000.

The city does have an oxygen plant, but it only produces between 100 and 160 tanks a day. The dean of the Medical College of Peru, Miguel Palacios, told local media that quantity is not enough and that current production would need to be tripled.

The priests’ campaign was launched the morning of May 3 on social media, and in less than a day, they had raised about $300,000.

Both priests thanked contributors, and said that thanks to the amount collected, a “high capacity” plant could be purchased for Iquitos.

Portelli added that Fuentes is currently in Lima coordinating with a specialist for the acquisition of the plant.

“Pray a lot that this work can be accomplished quickly. May God bless all who have contributed. We hope to continue to cover all the expenses,” he added.

  This story was first published by CNA's Spanish-language news partner, ACI Prensa. It has been translated and adapted by CNA.



 

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Behavioral economics applies key principles from psychology and economics to address obstacles to behavior change. The important topic of pediatric firearm injuries has not yet been explored through a behavioral economic lens. Pediatric firearm-related injuries are a significant public health problem in the United States. Despite American Academy of Pediatrics guidelines advising that firearms be stored unloaded, in a locked box or with a locking device, and separate from ammunition, estimates suggest that ~4.6 million children live in homes with at least 1 loaded and unlocked firearm. In this article, we use behavioral economic theory to identify specific cognitive biases (ie, present bias; in-group, out-group bias; and the availability heuristic) that may influence parental decision-making around firearm storage. We illustrate situations in which these biases may occur and highlight implementation prompts, in-group messengers, and increased salience as behaviorally informed strategies that may counter these biases and subsequently enhance safe firearm storage. We also describe other opportunities to leverage the behavioral economic tool kit. By better understanding the individual behavioral levers that may impact decision-making around firearm storage, behavioral scientists, pediatric providers, and public health practitioners can partner to design and test tailored interventions aimed at decreasing pediatric firearm injuries. Further empirical study is warranted to identify the presence of specific biases and heuristics and determine the most effective behavior change strategies for different subpopulations.

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