Intranasal antisepsis to reduce influenza virus transmission in an animal model.

BACKGROUND: Seasonal influenza annually causes significant morbidity and mortality, and unpredictable respiratory virus zoonoses, such as the current COVID-19 pandemic, can threaten the health and lives of millions more. Molecular iodine (I2 ) is a broad-spectrum, pathogen-nonspecific antiseptic agent that has demonstrated antimicrobial activity against a wide range of bacteria, virus, and fungi. METHODS: We investigated a commercially available antiseptic, a non-irritating formulation of iodine (5% povidone-iodine) with a film-forming agent that extends the duration of the iodine's antimicrobial activity, for its ability to prevent influenza virus transmission between infected and susceptible animals in the guinea pig model of influenza virus transmission. RESULTS: We observed that a once-daily topical application of this long-lasting antiseptic to the nares of either the infected virus-donor guinea pig or the susceptible virus-recipient guinea pig, or to the nares of both animals, prior to virus inoculation effectively reduced transmission of a highly transmissible influenza A virus, even when the donor and recipient guinea pigs shared the same cage. Daily treatment of the recipient guinea pig starting 1 day after initial exposure to an infected donor guinea pig in the same cage was similarly effective in preventing detectable influenza virus infection in the recipient animal. CONCLUSIONS: We conclude that a daily application of this antiseptic formulation is efficacious in reducing the transmission of influenza A virus in the guinea pig model, and further study in this and other preclinical models is warranted.

SOC-V-10 Hearing loss: side-effects of multiple compounds and formulations which can be monitored with functional and histological read-outs

Purpose: Hearing loss is a major global health issue affecting around 1.5 billion people worldwide, with an increasing prevalence. Acquired hearing loss is attributed to different environmental factors including ageing, noise exposure, and the intake of ototoxic medicines. Some commonly used medications can considerably affect the auditory system, resulting in cochlear and central damage that can lead to permanent hearing loss. More than 600 classes of medications are ototoxic. The most used in clinical practice are chemotherapeutics (cisplatin) and aminoglycoside antibiotics (such as gentamicin). Some investigated drugs for Covid-19 treatment (hydroxychloroquine, HCQ) and certain drug delivery agents like cyclodextrins (CD) have also been reported to induce auditory side effects. The aim of these in vivo studies was to provide functional and histological data on auditory assessments related to cisplatin, gentamicin, HCQ, and CD, when administered similarly to clinical protocol. Method(s): The studies were conducted in Wistar rats and Albino guinea pigs: * Cisplatin was administered by intraperitoneal route at 10 mg/kg in rats * Gentamicin was administered by intramuscular route at 160 mg/kg for 5 days in rats * HCQ was administered at 62 mg/kg per os daily for five days in rats * A cyclodextrin-based formulation was administered by transtym-panic route at 4 mg/mL 1 h and 30 h after noise exposure in guinea pigs Hearing was assessed using the techniques of Distortion Product Otoacoustic Emissions (DPOAE) and Auditory Brainstem Responses (ABR) at several timepoints. DPOAE are acoustic signals created and amplified by the cochlear epithelium and measured in the ear canal. DPOAE reflect the activity of outer hair cells (OHC). ABR is an electrophysiological measure of the sensorineural activity of the auditory pathway from the cochlea to the central auditory structures in response to a sound stimulus, recorded as electric potentials from scalp electrodes. A cochleogram, an FDA-recommended histological analysis for hair cell counting, was performed at the end of certain studies. Result(s): Results based on ABR thresholds, DPOAE amplitudes, and the cochleogram, showed different patterns of auditory side-effects. Cisplatin induced immediate and permanent hearing loss;gentamicin displayed delayed side-effects on auditory measures;HCQ did not affect Outer Hair Cells but might have had an effect on neurons. CD had an immediate and prolonged effect on hearing. Conclusion(s): This short presentation will help you learn the current available methods to measure hearing in preclinical in-vivo trials using two complementary functional read-outs and a histological analysis, and to determine the different sites of damage. Copyright © 2022 Elsevier B.V.

Zoonotic potential of guinea pigs: Outbreak of cryptosporidiosis combined with chlamydiosis in a breeding guinea pig herd.

INTRODUCTION: In a guinea pig herd with 26 breeding animals, several individuals of all age categories died (16/26) after three animals had been newly introduced from another herd. Furthermore, the population suffered of apathy, anorexia, severe weight loss and conjunctivitis, as well as abortions and stillbirths. At the same time, the owner experienced a SARS-CoV-2 infection with pneumonia, which was confirmed by taking a PCR test. Chlamydia caviae was detected from the conjunctiva and vagina/uterus in one juvenile animal together with an intestinal Cryptosporidium wrairi infection. Oocysts were found histologically in the small intestine, which was confirmed by PCR. C. wairi is a parasite adapted to guinea pigs with zoonotic potential, which causes diarrhoea with frequent deaths in larger guinea pig herds. C. caviae is also a zoonotic pathogen and often the cause of conjunctivitis, pneumonia and abortions in guinea pigs and can lead to upper respiratory tract disease, conjunctivitis but also severe pneumonia in humans. The increased death cases and the clinical signs could be traced back to an infection with Cryptosporidium wrairi, complicated by a co-infection of C. caviae. We suspect that the abortions were caused by C. caviae, but since the population was treated with various antibiotics effective against chlamydial infections, it was no longer possible to verify this by PCR testing. Unfortunately, more animals succumbed and finally only two animals of the originally 26 were left. With this case report, we would like to point out to veterinarians that guinea pigs can be an important source of zoonotic infections for various pathogens, especially since they are popular pets and often come into close contact with children where hygiene might not always be strictly followed.

INTRODUCTION: Dans un groupe de cobayes de 26 animaux reproducteurs, plusieurs individus de toutes les catégories d'âge sont morts (16/26) après l'introduction de trois animaux provenant d'un autre groupe. En outre, la population a souffert d'apathie, d'anorexie, de perte de poids sévère et de conjonctivite ainsi que d'avortements et de mortinatalité. La présence de Chlamydia caviae a pu être détectée dans la conjonctive et le vagin/utérus d'un animal juvénile, ainsi qu'une infection intestinale à Cryptosporidium wrairi. Des oocystes ont été trouvés histologiquement dans l'intestin grêle, ce qui a été confirmé par PCR. C. wairi est un parasite adapté aux cobayes avec un potentiel zoonotique, qui provoque des diarrhées avec des morts fréquentes dans les grands groupes de cobayes. C. caviae est également un agent pathogène zoonotique et est souvent à l'origine de conjonctivites, de pneumonies et d'avortements chez les cobayes ; il peut entraîner des maladies des voies respiratoires supérieures, des conjonctivites mais aussi des pneumonies graves chez l'homme. L'augmentation des cas de décès et les signes cliniques pourraient être attribués à une infection par Cryptosporidium wrairi, compliquée par une co-infection par C. caviae. Nous soupçonnons que les avortements ont été causés par C. caviae, mais comme la population a été traitée avec divers antibiotiques efficaces contre les infections à chlamydia, il n'était plus possible de le vérifier par des tests PCR. Malheureusement, d'autres animaux ont succombé et il ne restait finalement que deux animaux sur les 26 d'origine. Avec ce rapport de cas, nous aimerions attirer l'attention des vétérinaires sur le fait que les cochons d'Inde peuvent être une source importante d'infections zoonotiques pour divers pathogènes, d'autant plus qu'il s'agit d'animaux de compagnie populaires qui sont souvent en contact étroit avec des enfants avec lesquels l'hygiène n'est pas toujours strictement respectée.

Understanding barriers and facilitators to clinical trial participation among Black patients with multiple myeloma

Background: Currently, Black patients make up 20% of people living with multiple myeloma, yet they represent only 6% of participants in clinical trials.1 The underrepresentation of Black patients in clinical trials can contribute to outcome disparities thereby negatively impacting health equity in cancer treatment and outcomes.2 This project examined attitudes towards clinical trials among Black multiple myeloma patients and caregivers. Findings will inform the development of programs aimed at increasing clinical trial participation in this population. Methods: In 2021, the Cancer Support Community conducted an online survey to gain insights on barriers, facilitators, and perceptions of clinical trials among Black multiple myeloma patients and caregivers/care partners. Survey questions were informed by insights from prior focus groups. 94 patients and 101 caregivers were surveyed. Results: Most participants were male (62%) and African American (90%). 5% identified as African Caribbean and 5% as Black and Hispanic. The average age was 46 years. Just over half (51%) currently or previously participated in clinical trials. Of those who chose not to participate in a trial, the most common reasons were fear of side effects (46%) and fear of receiving a placebo (38%). Another barrier to participation reported was discomfort with being randomly assigned to a treatment (56%). Participants reported a significant level of distrust in medical research and doctors, saying that it was “very or somewhat likely” that doctors provide treatment as part of an experiment without patient consent (41%) and that they might be used as a “guinea pig” (25%). Of note, 57% of respondents said COVID had changed their attitude towards participating in clinical trials. 14 of 16 factors mentioned in our focus groups were affirmed by more than half of respondents as facilitating participation in a clinical trial. The top factors were: Understanding potential side effects (66%) My health care team speaks to me about trials (65%) Compensation offered for transportation, childcare, or time off work (62%) My family/community support my decision (61%). Conclusions: These findings are consistent with previous research which found that cancer patients reported the biggest attitudinal barriers to clinical trial participation were fear of side effects, distrust in medical research, and random assignment to clinical trial groups.3 Our study highlights that Blacks and African Americans living with multiple myeloma value multifactorial efforts to increase clinical trial participation: logistical and financial interventions, patient/provider communication, and culturally sensitive support and education programs. These programs can also work to improve health equity by reducing barriers to overall care and encouraging Blacks and African Americans living with multiple myeloma to be active members of their health care team.

Interleukin-6 Elevation Is a Key Pathogenic Factor Underlying COVID-19-Associated Heart Rate-Corrected QT Interval Prolongation.

Background: Heart rate-corrected QT interval (QTc) prolongation is prevalent in patients with severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. Recent evidence suggests that the exaggerated host immune-inflammatory response characterizing the disease, specifically interleukin-6 (IL-6) increase, may have an important role, possibly via direct effects on cardiac electrophysiology. The aim of this study was to dissect the short-term discrete impact of IL-6 elevation on QTc in patients with severe COVID-19 infection and explore the underlying mechanisms. Methods: We investigated the following mechanisms: (1) the QTc duration in patients with COVID-19 during the active phase and recovery, and its association with C-reactive protein (CRP) and IL-6 levels; (2) the acute impact of IL-6 administration on QTc in an in vivo guinea pig model; and (3) the electrophysiological effects of IL-6 on ventricular myocytes in vitro. Results: In patients with active severe COVID-19 and elevated IL-6 levels, regardless of acute myocardial injury/strain and concomitant QT-prolonging risk factors, QTc was significantly prolonged and rapidly normalized in correlation with IL-6 decrease. The direct administration of IL-6 in an in vivo guinea pig model acutely prolongs QTc duration. Moreover, ventricular myocytes incubated in vitro with IL-6 show evident prolongation in the action potential, along with significant inhibition in the rapid delayed rectifier potassium current (IKr). Conclusion: For the first time, we demonstrated that in severe COVID-19, systemic inflammatory activation can per se promote QTc prolongation via IL-6 elevation, leading to ventricular electric remodeling. Despite being transitory, such modifications may significantly contribute to arrhythmic events and associated poor outcomes in COVID-19. These findings provide a further rationale for current anti-inflammatory treatments for COVID-19, including IL-6-targeted therapies.

Disseminated Mycobacterium genavense infection in a guinea pig (Cavia porcellus): a case report.

BACKGROUND: Mycobacteria are found in many environmental conditions and infect a variety of species, including rodents and rabbits. Guinea pigs are used experimentally as a model for Mycobacterium tuberculosis, but natural mycobacteriosis in guinea pigs has not been reported. CASE PRESENTATION: A 1.5-year-old female guinea pig was found acutely deceased with no premonitory illness. On gross post-mortem examination, multifocal to coalescing, raised, firm, pale tan nodules with discrete, irregular margins were noted over the surfaces of all lung lobes. Histopathology revealed nodules composed of clustered foamy macrophages and multinucleated giant cells containing numerous bacterial rods. Similar bacteria-laden macrophages were noted within sections of the liver, heart, palpebral conjunctiva, duodenum, and cecum. Polymerase chain reaction was performed on tissues collected during post-mortem examination. The 16S rRNA gene product was sequenced and was identical to the Mycobacterium genavense type strain. CONCLUSIONS: To the best of the author's knowledge, this report details the first documented case of Mycobacterium genvaense infection in a guinea pig and a follow up investigation of close-contact animals. Given their experimental susceptibility and this clinical case report, mycobacteriosis should be considered as a differential in guinea pigs exhibiting weight loss in the absence of other clinical signs. With the potential for zoonotic transmission in immunosuppressed individuals, precautions should be taken to safeguard human health in cases of guinea pigs with suspected M. genavense infection.

Platelets factor 4 (PF4) binding enhances in vitro neutrophil extracellular traps (NET) capture of SARs-CoV- 2: Therapeutic implications

Background: SARs-CoV- 2 infection recruits high numbers of neutrophils that extrude neutrophil extracellular traps (NETs), webs of extracellular DNA coated with citrullinated histones (cit-His) and antimicrobial proteins. NETs have also been shown to entrap virions, concentrate antiviral proteins, and inactivate viruses. However, when NETs are degraded, they release NET degradation products (NDPs) such as cit-His, cell-free (cf) DNA, myeloperoxidase (MPO) and neutrophil elastase (NE) that can be toxic to the host. Our group and others have found that NETs and NDPs are highly prominent in patients with severe COVID-19 and are associated with the development of respiratory failure (Figure 1). Platelet factor 4 (PF4) is a highly-positively charged, platelet-specific chemokine that aggregates polyanionic molecules like heparin and DNA. We have shown that PF4 binds to NETs, reducing the release of NDPs by preventing NET digestion by circulating nucleases. Importantly, PF4-NET complexes markedly enhance gram-positive and -negative bacterial entrapment, likely by bridging the negatively charged polyanionic phosphoribose backbone of the NET DNA scaffold to polyanionic surface molecules in the bacterial cell wall. Treatment with PF4 improved outcomes in lipopolysaccharide endotoxemia and cecal ligation and puncture models of murine sepsis. Objectives: The objective of this study was to investigate whether PF4 binding to NETs is similarly protective in SARs-CoV- 2 infection by preventing the degradation of NETs and by enhancing NET-mediated viral capture. Methods: We generated NET-lined microfluidic channels. Neutrophils were isolated from healthy human donors, adhered to fibronectin-coated channels, and incubated with phorbol myristate acetate (PMA) to induce the release of NETs. Channels were then treated with buffer alone or PF4 (100 μg/ml) to compact NETs, after which gamma-irradiated SARS-CoV- 2 (1 x 107 PFU) were infused at 2 dynes/cm2 for 1 hour. Viral particles were then labeled with SARS-CoV- 2 guinea pig antiserum and visualized with a fluorescently-labeled secondary antibody. Viral binding to NETs was quantified using confocal microscopy. Results: Similar to that seen with bacterial attachment to NETs, we observed scant viral binding to non-compact NETs. In contrast, there was abundant binding of SARs-CoV- 2 aggregates to PF4 compacted NETs (Figure 2). Conclusions: These findings demonstrate that PF4 plays a crucial role in NET-mediated viral capture and suggest that PF4-NET complexes may be part of the physiologic mechanism by which viral spread is contained in the host. Moreover, we have previously shown that an Fc-modified version of KKO, a monoclonal antibody directed against complexes of PF4 and polyanions, markedly enhanced the protective effects of PF4 in vitro and in murine models of sepsis. Therefore, we will examine whether PF4 plus modified KKO infusions are able to limit SARS-CoV- 2 viremia, preventing the pneumonitis and multi-system organ dysfunction of severe COVID-19. (Figure Presented).

Zika Virus and Host Interactions: From the Bench to the Bedside and Beyond.

Before the emergence of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the causative agent of the current COVID-19 (coronavirus disease 2019) pandemic [...].