Monkeypox is a zoonotic viral disease. Monkeypox was first reported in humans about 54 years ago. Prior to the global outbreak, monkeypox was endemic to the rainforests of central and western African countries. In the last three years, increasing numbers of human monkeypox have been reported from various countries. Responding to the severity, monkeypox was declared a Public Health Emergency of International Concern by the World Health Organization. In the absence of approved drugs or clinical studies, repurposed drugs and therapeutic medical countermeasures effective against other orthopoxviruses have been utilized to treat severe human monkeypox cases. Currently, clinical trials are underway exploring the potential therapeutic effectiveness of tecovirimate in human monkeypox cases. Monoclonal antibodies, IFN-β, resveratrol, and 15 triple-targeting FDA-approved drugs represent potential new drug targets for human monkeypox, necessitating further research.

Brincidofovir (BCV) is a lipid conjugate of cidofovir with good oral bioavailability, enabling optimal intracellular levels of the active drug. Lower rates of nephrotoxicity and myelotoxicity make it a favorable alternative. Despite a greater safety profile among pediatric hematopoietic cell transplant recipients, the oral formulation has been associated with increased gastrointestinal toxicity in adult hematopoietic cell transplant recipients. Oral BCV continues to be developed as a countermeasure against smallpox, while a potentially safer intravenous preparation has been out licensed to another company. BCV has demonstrated great in vitro potency against double-stranded DNA viruses, especially adenovirus. Because of its importance for immunocompromised patients, this review aims to evaluate BCV\'s clinical and safety profile to support its continued development.

A national control program against bovine respiratory syncytial virus (BRSV) and bovine coronavirus (BCV) was launched in Norway in 2016. A key strategy in the program is to test for presence of antibodies and protect test-negative herds from infection. Because these viruses are endemic, the rate of re-introduction can be high, and a disease-free status will become more uncertain as time from testing elapses. The aim of this study was to estimate the probability of freedom (PostPFree) from BRSV and BCV antibodies over time by use of bulk tank milk (BTM) antibody-testing, geographic information and animal movement data, and to validate the herd-level estimates against subsequent BTM testing. BTM samples were collected from 1148 study herds in West Norway in 2013 and 2016, and these were analyzed for BRSV and BCV antibodies. PostPFree was calculated for herds that were negative in 2013/2014, and updated periodically with new probabilities every three months. Input variables were test sensitivity, the probability of introduction through animal purchase and local transmission. Probability of introduction through animal purchase was calculated by using real animal movement data and herd prevalence in the region of the source herd. The PostPFree from the final three months in 2015 was compared to BTM test results from March 2016 using a Wilcoxon Rank Sum Test. The probability of freedom was generally high for test-negative herds immediately after testing, reflecting the high sensitivity of the tests. It did however, decrease with time since testing, and was greatly affected by purchase of livestock. When comparing the median PostPFree for the final three months to the test results in 2016, it was significantly lower (p < 0.01) for test positive herds. Furthermore, there was a large difference in the proportion of test positive herds between the first and fourth quartile of PostPFree. The results show that PostPFree provides a better estimate of herd-level BTM status for both BRSV and BCV than what can be achieved by relying solely on the previous test-result.

Bovine respiratory syncytial virus (BRSV) and bovine coronavirus (BCV) are responsible for respiratory disease and diarrhea in cattle worldwide. The Norwegian control program against these infections is based on herd-level diagnosis using a new multiplex immunoassay. The objective of this study was to estimate sensitivity and specificity across different cut-off values for the MVD-Enferplex BCV/BRSV multiplex, by comparing them to a commercially available ELISA, the SVANOVIR® BCV-Ab and SVANOVIR® BRSV-Ab, respectively. We analyzed bulk tank milk samples from 360 herds in a low- and 360 herds in a high-prevalence area. As none of the tests were considered perfect, estimation of test characteristics was performed using Bayesian latent class models. At the manufacturers\' recommended cut-off values, the median sensitivity for the BRSV multiplex and the BRSV ELISA was 94.4 [89.8-98.7 95% Posterior Credibility Interval (PCI)] and 99.8 [98.7-100 95% PCI], respectively. The median specificity for the BRSV multiplex was 90.6 [85.5-94.4 95% PCI], but only 57.4 [50.5-64.4 95% PCI] for the BRSV ELISA. However, increasing the cut-off of the BRSV ELISA increased specificity without compromising sensitivity. For the BCV multiplex we found that by using only one of the three antigens included in the test, the specificity increased, without concurrent loss in sensitivity. At the recommended cut-off this resulted in a sensitivity of 99.9 [99.3-100 95% PCI] and specificity of 93.7 [88.8-97.8 95% PCI] for the multiplex and a sensitivity of 99.5 [98.1-100 95% PCI] and a specificity of 99.6 [97.6-100 95% PCI] for the BCV ELISA.

Adenovirus infection in immunocompromised patients contributes to significant morbidity and mortality, especially after allogeneic hematopoietic cell transplantation (HCT). Brincidofovir (BCV, CMX001) is an orally bioavailable lipid conjugate of cidofovir that has in vitro activity against adenoviruses and other double-stranded DNA viruses. This randomized placebo-controlled phase II trial evaluated pre-emptive treatment with BCV for the prevention of adenovirus disease in pediatric and adult allogeneic HCT recipients with asymptomatic adenovirus viremia. Allogeneic HCT recipients with adenovirus viremia were randomized 1:1:1 to receive oral BCV 100 mg (2 mg/kg if <50 kg) twice weekly (BIW), BCV 200 mg (4 mg/kg if <50 kg) once weekly (QW), or placebo for 6 to 12 weeks, followed by 4 weeks of post-treatment follow-up. For randomization, subjects were stratified by screening absolute lymphocyte count (<300 cells/mm3 versus ≥300 cells/mm3). Assignment to BCV or placebo was double blinded; dose frequency was unblinded. The primary endpoint was the proportion of subjects experiencing treatment failure, defined as either progression to probable or definitive adenovirus disease or confirmed increasing adenovirus viremia (≥1 log10 copies/mL) during randomized therapy. Between June 2011 and December 2012, 48 subjects were randomized to the BCV BIW (n = 14), BCV QW (n = 16), or placebo (n = 18) groups. The proportion of subjects with treatment failure in the BCV BIW group was 21% (odds ratio, .53; 95% confidence interval [CI], .11 to 2.71; P = .45), 38% (odds ratio, 1.23; 95% CI, .30 to 5.05, P = .779) in the BCV QW group, and 33% in the placebo group. All-cause mortality was lower in the BCV BIW (14%) and BCV QW groups (31%) relative to the placebo group (39%), but these differences were not statistically significant. After 1 week of therapy, 8 of 12 subjects (67%) randomized to BCV BIW had undetectable adenovirus viremia (<100 copies/mL), compared with 4 of 14 subjects (29%) randomized to BCV QW and 5 of 15 subjects (33%) randomized to placebo. In a post hoc analysis of subjects with viremia ≥1000 copies/mL at baseline, 6 of 7 BCV BIW subjects (86%) achieved undetectable viremia compared with 2 of 8 placebo subjects (25%; P = .04). Early treatment discontinuation because of adverse events was more common in subjects treated with BCV than with placebo. Diarrhea was the most common event in all groups (57% BCV BIW, 38% BCV QW, 28% placebo), but it led to treatment discontinuation in only 1 subject receiving BCV QW. Events diagnosed as acute graft-versus-host disease, primarily of the gastrointestinal tract, were more frequent in the BCV BIW group (50%) than in the BCV QW (25%) and placebo (17%) groups. There was no evidence of myelotoxicity or nephrotoxicity in BCV-treated subjects. The results of this trial confirm the antiviral activity of BCV against adenoviruses. Further investigation is ongoing to define the optimal treatment strategy for HCT recipients with serious adenovirus infection and disease.

BACKGROUND: Bovine coronavirus (BCoV) is a widely distributed pathogen, causing disease and economic losses in the cattle industry worldwide. Prevention of virus spread is impeded by a lack of basic knowledge concerning viral shedding and transmission potential in individual animals. The aims of the study were to investigate the duration and quantity of BCoV shedding in feces and nasal secretions related to clinical signs, the presence of virus in blood and tissues and to test the hypothesis that seropositive calves are not infectious to naïve in-contact calves three weeks after BCoV infection.
METHODS: A live animal experiment was conducted, with direct contact between animal groups for 24 h as challenge procedure. Four naïve calves were commingled with a group of six naturally infected calves and sequentially euthanized. Two naïve sentinel calves were commingled with the experimentally exposed group three weeks after exposure. Nasal swabs, feces, blood and tissue samples were analyzed for viral RNA by RT-qPCR, and virus isolation was performed on nasal swabs. Serum was analyzed for BCoV antibodies.
RESULTS: The calves showed mild general signs, and the most prominent signs were from the respiratory system. The overall clinical score corresponded well with the shedding of viral RNA the first three weeks after challenge. General depression and cough were the signs that correlated best with shedding of BCoV RNA, while peak respiratory rate and peak rectal temperature appeared more than a week later than the peak shedding. Nasal shedding preceded fecal shedding, and the calves had detectable amounts of viral RNA intermittently in feces through day 35 and in nasal secretions through day 28, however virus isolation was unsuccessful from day six and day 18 from the two calves investigated. Viral RNA was not detected in blood, but was found in lymphatic tissue through day 42 after challenge. Although the calves were shedding BCoV RNA 21 days after infection the sentinel animals were not infected.
CONCLUSIONS: Prolonged shedding of BCoV RNA can occur, but detection of viral RNA does not necessarily indicate a transmission potential. The study provides valuable information with regard to producing scientifically based biosecurity advices.

BACKGROUND: A percutaneous intravascular cardioverter-defibrillator (PICD) has been developed with a right ventricular (RV) single-coil lead and titanium electrodes in the superior vena cava (SVC)-brachiocephalic vein (BCV) region and the inferior vena cava (IVC).
OBJECTIVE: To compare defibrillation thresholds (DFTs) of the PICD with those of a conventional ICD in humans.
METHODS: Ten patients with ischemic cardiomyopathy and ejection fraction ≤35% were randomized to initial testing with either PICD or conventional ICD. A standard dual-coil lead was positioned in the RV apex. If randomized to PICD, the device was placed into the vasculature such that 1 titanium electrode was positioned in the SVC-BCV region and the second in the IVC. For PICD DFTs, the RV coil of the conventional ICD lead was connected to the PICD mandrel [shock vector: RV (+) to SVC-BCV (-) + IVC (-)]. When testing the conventional ICD, a subcutaneous pocket was formed in the left pectoralis region and the ICD was connected to the lead system and positioned in the pocket [shock vector: RV (+) to SVC (-) + active can (-)]. Each device was removed before testing with the other. A step-down binary search protocol determined the DFT, with the initial shock being 9 J.
RESULTS: The mean PICD DFT was 7.6 ± 3.3 J, and the conventional ICD system demonstrated a mean DFT of 9.5 ± 4.7 J (N = 10; paired t test, P = .28).
CONCLUSIONS: The intravascular defibrillator has DFTs similar to those of commercially available ICDs.

Waddlia chondrophila is an emerging pathogen causing miscarriages in humans and abortions in ruminants. The full genome of this Chlamydia-related bacterium has been recently completed, providing new insights into its biology and evolution. Moreover, new cell biology approaches and the use of novel inhibitors have allowed detailed investigations of its interaction with host cells.

Leishmaniasis threatens more than 350 million people worldwide specially in tropical and subtropical region. Antileishmanial drugs that are currently available have various limitations. The search of new drugs from natural products (plants, animals) possessing antileishmanial activity is ventured throughout the world. The present study deals with the antileishmanial activity of Bungarus caeruleus snake venom (BCV) on in vitro promastigotes and amastigotes of Leishmania donovani parasite and leishmania infected BALB/c mice. The effect of BCV on peritoneal macrophage, release of cytokines from the activated macrophages, production of nitric oxide, reactive oxygen species and cytokines were studied in vivo and in vitro. IC50 value of BCV on L. donovani promastigote was 14.5 μg/ml and intracellular amastigote was 11.2 μg/ml. It activated peritoneal macrophages, significantly increased cytokines and interleukin production. BCV (20 μg/kg and 40 μg/kg body weight of mice) decreased parasite count by 54.9% and 74.2% in spleen and 41.4% and 60.4% in liver of infected BALB/c mice. BCV treatment significantly increased production of TNF-α, IFN-γ, ROS, NO in infected mice. Histological studies showed decreased granuloma formation in treated liver as compared with control. Liver and spleen structure was partially restored due to BCV treatment in infected mice. The present study revealed that BCV possessed antileishmanial activity against L. donovani parasite in vivo and in vitro and this activity was partly mediated through immunomodulatory activity involving macrophages.

Various theories suggest endolymphatic hydrops may cause a rupture of the membranous labyrinth or may force open the utriculo-saccular duct, resulting in a sudden change in inner ear function. Here, we have used slow injections of artificial endolymph into either scala media or the utricle of anaesthetised guinea pigs to investigate the effects of hydrops. Vestibular function was continuously monitored in addition to the measurements of cochlear function developed in our laboratory (Brown et al. Hear Res, 2013). Scala media injection induced consistent functional changes, which occurred in two stages. Initial changes involved were associated with an increased hydrostatic pressure in scala media that only affected cochlear function. After 3-4 μl of endolymph had been injected, cochlear function spontaneously recovered, and was often shortly followed by a transient increase or decrease in utricular sensitivity, with the effects varying between animals. Endolymph injection directly into the utricle produced variable effects across animals, although in 2 experiments it produced similar changes as those observed for scala media injections, suggesting that the fluid pathway between scala media and the utricle was continuous in these animals. The mechanism underlying the sudden, spontaneous functional changes is not yet clear, but we tentatively suggest that in some cases it may be caused by the utriculo-saccular duct suddenly opening to alleviate an elevated hydrostatic pressure in the pars inferior, resulting in a change in utricular function due to an increase in its volume. These changes are comparable to the sudden or fluctuating functional changes in Ménière\'s sufferers, and support the hypothesis that endolymphatic hydrops can directly cause some symptoms of this syndrome.