Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis.

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.

Treatment of Mycobacterium avium complex pulmonary disease (MAC-PD) is challenging partly due to high efflux pump expression. Thioridazine might block these efflux pumps. We explore thioridazine's efficacy against M. avium using minimum inhibitory concentrations (MICs), time-kill combination assays, ex vivo macrophage infection assays and efflux assays. Thioridazine is bactericidal against M. avium, inhibits intracellular growth at 2x MIC and blocks ethidium bromide efflux. However, its toxicity and low plasma concentrations, make it unlikely to add efficacy to MAC-PD therapy.

Staphylococcus aureus osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathologic bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit S. aureus quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because diflunisal's "quorum-quenching" activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard of care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis, and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of diflunisal in vitro and in vivo. Similarly, locally-delivered diflunisal still potently inhibits osteoblast cytotoxicity in vitro and bone destruction in vivo in the presence of sub-therapeutic vancomycin. However, we also found that the resorbable polyurethane foams used to deliver diflunisal serve as a nidus for infection. Taken together, these data demonstrate that diflunisal does not significantly impact standard of care antibiotic therapy for S. aureus osteomyelitis, but also highlight potential pitfalls encountered with local drug delivery.

Background: MRSA pose significant therapeutic challenges, related to their: frequency in clinical infections; innate virulence properties; and propensity for multi-antibiotic resistance. MRSA are among the most common causes of endovascular infections, including infective endocarditis (IE).

Objective: To employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE.

Study Design: TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (vs daptomycin alone). Primary intravegetation outcomes were: maximum size; weights at sacrifice; and MRSA counts at infection baseline vs after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment Day 1).

Results: A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase + daptomycin vs the daptomycin-alone therapy groups (p = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower vs daptomycin-alone (p < 0.0001). Maximum vegetation size by TTE correlated with vegetation weight (p = 0.005). In addition, intravegetation MRSA counts in the combination group were significantly lower vs untreated controls (p<0.0001) and the daptomycin-alone group (p<0.0001).

Conclusion: This study suggests that exebacase has a salutary impact on MRSA-infected vegetation progression when combined with daptomycin, especially in terms of vegetation MRSA burden, size and weight. Moreover, TTE appears to be an efficient non-invasive tool to assess therapeutic efficacies in experimental MRSA IE.

Two non-amidated host defence peptides named Pin2[G] and FA1 were evaluated against three types of pathogenic bacteria; two isolated from diabetic foot ulcer patients, Staphylococcus aureus UPD13 and Pseudomonas aeruginosa UPD3, and another from a commercial collection, Salmonella enterica serovar Typhimurium (ATCC 14028). In vitro experiments showed that the antimicrobial performance of the synthetic peptides, Pin2[G] and FA1, was modest, although FA1 was more effective than Pin2[G]. In contrast Pin2[G] had superior in vivo anti-infective activity to FA1 in rabbit wound infections by the diabetic foot ulcer pathogens S. aureus UPD13 and P. aeruginosa UPD3. Indeed, Pin2[G] reduced bacterial colony counts of both S. aureus UPD13 and P. aeruginosa UPD3 by >100,000-fold after 48-72 h on skin wounds of infected rabbits, while in similar infected wounds, FA1 had no major effects at 72-96 h of treatment. Ceftriaxone was equally effective vs. Pseudomonas but less effective vs. S. aureus infections. Additionally, the two peptides were evaluated in mice against intragastrically inoculated S. enterica ser. Typhimurium (ATCC 14028). Only Pin2[G], at 0.56 mg/kg, was effective in reducing systemic (liver) infection by >67-fold, equivalent to the effect of treatment with levofloxacin. Pin2[G] showed superior immunomodulatory activity in increasing chemokine production by a human bronchial cell line and suppressing poly(IC)-induced pro-inflammatory IL6 production. These data showed that the in vitro antimicrobial activity of these peptides was not correlated with their in vivo anti-infective activity, and suggest that other factors such as immunomodulatory activity were more important.

Background

Optimal concentrations of unbound antimicrobials are essential for maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model.

Methods

Design

Prospective, three phase intervention observational study.

Subjects

Healthy Merino sheep.

Interventions

Eight sheep were subject to three experimental phases; normoalbuminemia, hypoalbuminemia using plasmapheresis and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone 40 mg/kg and ertapenem 15 mg/kg were given intravenously. Blood samples were collected at pre-defined intervals and analyzed using an ultra-high-performance liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters such as area under the curve (AUC_0-24), plasma clearance (CL) and apparent volume of distribution in the terminal phase (V_d) were estimated and compared between the phases.

Results

The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC_0-24 and higher CL of total and unbound concentrations of ceftriaxone compared to the other phases. Whereas albumin replacement led to higher AUC_0-24 and lower CL compared to other phases for both drugs. The V_d for total drug concentrations for both drugs were significantly lower with albumin replacement.

Conclusions

For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

The records involved conversation logs between Microsoft support agents and customers across the globe, dating back to 2005. Most of the records were redacted of customer contact information, but not all.

On Tuesday, Avast responded to a PCMag-Motherboard investigation into the company's browser history collection practices, saying it was entirely legal. Avast users should expect to see a prompt from the antivirus products, asking them to consent to the data harvesting.

Funders have been both fast and thoughtful about how to work with national and local partners to listen to needs from the field, identify best practices, and deploy resources quickly, says Celine Coggins.

"This pandemic has given us an opportunity to think boldly about students' educational needs and how to creatively respond to them," says Katherine Haley.

BACKGROUND:

Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo.

OBJECTIVES:

Infantile hemangiomas (IHs) are common; some cases require timely referral and treatment to prevent complications. We developed and validated a reliable instrument for timely and adequate referral of patients with IH to experts by nonexpert primary physicians.

True to its name, Home Chef is the homiest of meal services we've tried. The recipes are simple and not too adventurous, but for some home chefs, that's a good thing.

The start of the knockout rounds provided a reminder there is still plenty of value to be found at the defensive end of the field.

The Penn State Smeal College of Business Center for the Business of Sustainability recently hosted the first in a series of virtual fireside discussions titled “The Impact of Coronavirus on Sustainability and Social Impact,” to explore how recent momentum in sustainability efforts has been altered.

Using their unique skills and experiences, three LaunchBox grant recipients are providing a variety of COVID-19 relief efforts.

Millicent Collins
Aug 1, 2017; 140:e20160719-e20160719
CASE REPORTS

Germany's Shekiera Martinez, at 16, has written herself into UEFA's record books by scoring nine goals in a final tournament.

Cristiano Ronaldo's overhead kick for Real Madrid against his current club Juventus has been voted UEFA.com Goal of the Season.

Africa can be a challenging place to do business and property investment is not exempt from some, often unique, challenges, says a Nedbank expert.

Many teachers scrapped their lesson plans on Monday and gave their students space to talk about Kobe Bryant.

The 55-vehicle Volkswagen fleet which will transport players and officials at UEFA Futsal EURO 2018 has been handed over to the tournament organisers.

Hosts Slovenia have been handed a tough group with Italy and Serbia while France's debut finals match will be against holders Spain after the draw was made in Ljubljana.

Tickets are now on sale for UEFA Futsal EURO 2018 at Stožice Arena in Ljubljana with the first one bought by UEFA President Aleksander Čeferin, who was born in the Slovenian capital.

We look at the 12 teams that will compete in Slovenia between 30 January and 10 February – from champions Spain and former winners Italy and Russia to debutants France.

The official UEFA Futsal EURO 2018 programme, featuring all you need to know about the teams plus interviews with the likes of Wissam Ben Yedder, is out now and available to download for free.

You can watch UEFA Futsal EURO 2018 across Europe and the world thanks to UEFA's broadcast partners and the live streaming of games on UEFA.com and our YouTube channel UEFA.tv.

The UEFA Futsal EURO is to be expanded to 16 teams and will become a tournament played every four years, starting from 2022.

See all the results and highlights from UEFA Futsal EURO 2018 at Ljubljana's Stožice Arena.

A new Council of the Great City Schools effort aims to fill in a training gap for an important constituency: school boards.

CONTEXT:

Pneumococcal conjugate vaccines (PCVs) (pneumococcal 13-valent conjugate vaccine [PCV-13] and pneumococcal 10-valent conjugate vaccine [PCV-10]) are available for prevention of pneumococcal infections in children.

The UEFA Futsal Cup elite round runs from Wednesday to Sunday, with holders Inter FS and former champions Kairat Almaty and Barcelona among those chasing four available finals spots.

The 10,700-capacity Pabellón Príncipe Felipe in Zaragoza will host the UEFA Futsal Cup finals in April involving Spain's Inter FS and Barcelona plus Portugal's Sporting CP and Győr of Hungary.

The UEFA Futsal EURO is to be expanded to 16 teams and will become a tournament played every four years, starting from 2022.

Tickets for the UEFA Futsal Cup finals at Zaragoza's Pabellón Príncipe Felipe on 20, 22 April are on sale.

Apple quietly revealed new iPods today with new colors and better specs.

Before there were smartwatches, digital watches were the most high-tech timepieces you could buy. We explore the evolution of the digital watch from 1972 to present day.

Whether you want a customizable full-size tower or a mini PC, there's something for nearly every budget. Here are the best refurbished desktop deals for January 2020.

At Amazon right now, you can save up to 47 percent on a Samsung Q60 series QLED 4K Ultra HD smart TV with HDR support and Alexa and Google Assistant compatibility.

Before inviting everyone over to watch, make sure your TV setup is Super Bowl ready. After all, there's no excuse with sales like these.

SEVEN weeks into lockdown it’s natural that we’re all looking for the dove with the olive branch signifying this virus is receding. I fear, though, that a generation will pass before we encounter anything resembling normality. I’d be wary too of those eagerly plotting road-maps out of uncertainty and consider first what might lie behind their enthusiasm.

If researchers hope to identify programs that will prepare students for the future, then they cannot continue to measure innovation based on the ideas from the past.

Graham A. Colditz
Jul 1, 1995; 96:29-35
ARTICLES

Richard A. Ehrenkranz
Dec 1, 2005; 116:1353-1360
ARTICLES

Merle McPherson
Jul 1, 1998; 102:137-139
COMMENTARY

UEFA and Booking.com have announced a four-year global partnership for all UEFA national team football competitions from 2018 to 2022, including UEFA EURO 2020.