Effect of moxibustion on knee joint stiffness characteristics in recreational athletes pre- and post-fatigue.

Objective: Joint stiffness results from the coupling of the nervous system and joint mechanics, and thus stiffness is a comprehensive representation of joint stability. It has been reported that moxibustion can alleviate general weakness and fatigue symptoms and subsequently may influence joint stiffness. This study investigated whether moxibustion could enhance knee joint stiffness in recreational athletes pre- and post-fatigue. Methods: Eighteen participants were randomized into intervention (5 males: 20.6 ± 1.5 yr; 4 females: 20.8 ± 1.5 yr) and control groups (5 males: 19.4 ± 0.9 yr; 4 females: 20.5 ± 0.6 yr). The intervention group received indirect moxibustion applied to acupoints ST36 (bilateral) and CV4 for 30 min every other day for 4 consecutive weeks. The control group maintained regular exercise without moxibustion. Peak torque (PT) of right knee extensor, relaxed and contracted muscle stiffness (MS) of vastus lateralis, and knee extensor musculoarticular stiffness (MAS) was assessed with an isokinetic dynamometer (IsoMed 2000), myometer, and free oscillation technique, respectively. Measurements were taken at three time points: pre-intervention, post-intervention/pre-fatigue, and post-fatigue. Results: MAS (P = 0.006) and PT (P = 0.007) in the intervention group increased more from pre-to post-intervention compared with the control group. Post-fatigue MAS (P = 0.016) and PT (P = 0.031) increased more in the intervention group than in the control group. Conclusion: Moxibustion enhanced PT and knee MAS, suggesting that this intervention could be used in injury prevention and benefit fatigue resistance in young recreational athletes.

Development of a Novel Canine Parvovirus Vaccine Capable of Stimulating Protective Immunity in Four-Week-Old Puppies in the Face of High Levels of Maternal Antibodies.

Many highly effective vaccines have been developed to protect dogs against disease caused by canine parvovirus, but despite this vaccine interference by maternally derived antibodies continues to cause immunisation failure. To help overcome this limitation we have developed a novel, recombinant canine parvovirus type 2c vaccine strain, based on the structural and non-structural elements of an established type 2 vaccine. This novel CPV-2c vaccine strain has unique efficacy in the field, it is able to induce sterilising immunity in naïve animals 3 days after vaccination and is able to overcome very high levels of maternally derived antibodies from 4 weeks of age-thus closing the immunity gap to canine parvovirus infection in young puppies. The vaccine strain, named 630a, has been combined with an established canine distemper virus Onderstepoort vaccine strain to produce a new bivalent vaccine (Nobivac DP PLUS), intended to immunise very young puppies in the face of high levels of maternally derived antibody. Here, we describe the onset of immunity and maternal antibody interference studies that support the unique efficacy of the strain, and present overdose studies in both dogs and cats that demonstrate the vaccine to be safe.

Understanding the disease and economic impact of avirulent avian paramyxovirus type 1 (APMV-1) infection in Great Britain.

Newcastle disease (ND) is a notifiable disease affecting chickens and other avian species caused by virulent strains of Avian paramyxovirus type 1 (APMV-1). While outbreaks of ND can have devastating consequences, avirulent strains of APMV-1 generally cause subclinical infections or mild disease. However, viruses can cause different levels of disease in different species and virulence can evolve following cross-species transmission events. This report describes the detection of three cases of avirulent APMV-1 infection in Great Britain (GB). Case 1 emerged from the 'testing to exclude' scheme in chickens in Shropshire while cases 2 and 3 were made directly from notifiable avian disease investigations in chicken broilers in Herefordshire and on premises in Wiltshire containing ducks and mixed species, respectively). Class II/genotype I.1.1 APMV-1 from case 1 shared 99.94% identity to the Queensland V4 strain of APMV-1. Class II/genotype II APMV-1 was detected from case 2 while the class II/genotype I.2 virus from case 3 aligned closely with strains isolated from Anseriformes. Exclusion of ND through rapid detection of avirulent APMV-1 is important where clinical signs caused by avirulent or virulent APMV-1s could be ambiguous. Understanding the diversity of APMV-1s circulating in GB is critical to understanding disease threat from these adaptable viruses.

Discovery of Sulanemadlin (ALRN-6924), the First Cell-Permeating, Stabilized α-Helical Peptide in Clinical Development.

We report the discovery of sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-helical peptide to enter clinical trials. ALRN-6924 is a "stapled peptide" that mimics the N-terminal domain of the p53 tumor suppressor protein. It binds with high affinity to both MDM2 and MDMX (also known as MDM4), the endogenous inhibitors of p53, to activate p53 signaling in cells having a non-mutant, or wild-type TP53 genotype (TP53-WT). Iterative structure-activity optimization endowed ALRN-6924 with favorable cell permeability, solubility, and pharmacokinetic and safety profiles. Intracellular proteolysis of ALRN-6924 forms a long-acting active metabolite with potent MDM2 and MDMX binding affinity and slow dissociation kinetics. At high doses, ALRN-6924 exhibits on-mechanism anticancer activity in TP53-WT tumor models. At lower doses, ALRN-6924 transiently arrests the cell cycle in healthy tissues to protect them from chemotherapy without protecting the TP53-mutant cancer cells. These results support the continued clinical evaluation of ALRN-6924 as an anticancer and chemoprotection agent.

A Critical Review of Icosapent Ethyl in Cardiovascular Risk Reduction.

Icosapent ethyl (IPE) was the first fish oil product the US Food and Drug Administration (FDA) approved to reduce the risk of atherosclerotic cardiovascular disease (ASCVD) in adults. IPE is an esterified version of eicosapentaenoic acid (EPA) and acts as a prodrug in the body to exert its effects. IPE affects the body primarily through triglyceride (TG) reduction and was initially indicated for hypertriglyceridemia in addition to statin therapy or for patients with statin intolerances. Various studies have investigated this agent, and multiple subanalyses have been conducted since the FDA approval. These subanalyses have assessed factors such as sex, statin therapy, high-sensitivity C-reactive protein levels (hs-CRP), and various inflammatory biomarkers in groups of patients taking IPE. This article aims to provide a critical review of the clinical data available regarding cardiovascular benefits of IPE in patients with ASCVD and its value as a treatment option for patients with elevated TG levels.

Game Birds Can Act as Intermediaries of Virulent Genotype VII Avian Orthoavulavirus-1 between Wild Birds and Domestic Poultry.

Newcastle Disease (ND), caused by virulent forms of Avian orthoavulavirus serotype-1 (AOAV-1) is an economically important avian disease worldwide. The past two incursions of ND into the United Kingdom occurred in game bird populations during 2005 and 2006. The nature of the game bird semi-feral rearing system, which can bring these birds into close contact with both wild birds and commercial or backyard poultry, has been hypothesized to act as a bridge between these two environments. As such, the risk that AOAV-1-infected game birds may pose to the UK poultry industry was investigated. Pheasants, partridges and chickens were experimentally infected with the virulent strain APMV-1/Chicken/Bulgaria/112/13, a genotype VII.2 virus associated with ND outbreaks in Eastern Europe. The study demonstrated that both chickens and pheasants are susceptible to infection with APMV-1/Chicken/Bulgaria/112/13, which results in high mortality and onward transmission. Partridges by contrast are susceptible to infection, but mortality was reduced, as was onward transmission. However, the data indicated that both pheasants and partridges may serve as intermediate hosts of AOAV-1 and may bridge the wild bird-domestic poultry interface enabling transmission into an economically damaging environment where morbidity and mortality may be high.

A risk assessment of equine piroplasmosis entry, exposure and consequences in the UK.

BACKGROUND: Equine piroplasmosis (EP) is currently not endemic in the UK, despite a lack of formal surveillance and the presence of carrier horses in the equine population. Pathogen establishment would have significant welfare and economic impacts on the national equine industry, but the disease is often overlooked by UK practitioners. OBJECTIVES: To assess the risk of disease entry, exposure and consequences to the UK equine population. STUDY DESIGN: Qualitative risk assessment. METHODS: A qualitative risk assessment was constructed utilising the current World Organisation for Animal Health (OIE) published framework for importation risk assessment, assessing the key areas of disease entry, exposure and consequences to the UK equine population. RESULTS: The overall risk of EP entry to the UK via importation of infected equidae with acute disease is very low but considered medium with subclinical carrier animals. Entry via importation of ticks or the importation of blood is considered very low. The risk of EP exposure to susceptible equidae in the UK is considered low by the infection routes of tick-bites, contaminated needles and contaminated blood, but very high via transplacental transfer. However, the consequences of EP endemic establishment are considered of high significance to the UK equine industry. MAIN LIMITATIONS: A lack of available numerical data for events and variables in disease import risk meant a qualitative assessment was the most practical method for this scenario. CONCLUSIONS: This risk assessment highlights that EP positive animals are able to enter and are currently present in the UK, and that conditions do exist that could allow forward transmission of the disease. It has highlighted a gap in existing policy where the UK falls behind OIE guidelines and has suggested steps to correct this discrepancy and improve national biosecurity.

Comparative pathogenesis of two genotype VI.2 avian paramyxovirus type-1 viruses (APMV-1) in pheasants, partridges and chickens.

Newcastle disease (ND) is caused by virulent forms of avian paramyxovirus-1 (APMV-1) and is an economically important disease of poultry world-wide. Pigeon paramyxovirus 1 (PPMV-1), a sub-group of APMV-1 is endemic in Columbiformes and can cause infections of poultry. An outbreak of ND in partridges in Scotland, UK, in 2006 (APMV-1/partridge/UK(Scotland)/7575/06) was identified as a class II, genotype VI.2.1.1.2.1, more commonly associated with PPMV-1. It has been hypothesized that game birds may be a route of transmission into commercial poultry settings due to the semi-feral rearing system, which potentially brings them into contact with both wild-birds and poultry species. Therefore, the pathogenesis and transmission of APMV-1/partridge/UK(Scotland)/7575/06 in game birds and chickens was investigated, and compared to a contemporary PPMV-1 isolate, PPMV-1/pigeon/UK/015874/15. Viral shedding and seroconversion profiles demonstrated that pheasants were susceptible to infection with APMV-1/partridge/UK(Scotland)/7575/06 with limited clinical signs observed although they were able to excrete and transmit virus. In contrast, partridges and pheasants showed limited infection with PPMV-1/pigeon/UK/015874/15, causing mild clinical disease. Chickens, however, were productively infected and were able to transmit virus in the absence of clinical signs. From the data, it can be deduced that whilst game birds may play a role in the transmission and epidemiology of genotype VI.2 APMV-1 viruses, the asymptomatic nature of circulation within these species precludes evaluation of natural infection by clinical surveillance. It therefore remains a possibility that genotype VI.2 APMV-1 infection in game birds has the potential for asymptomatic circulation and remains a potential threat to avian production systems.RESEARCH HIGHLIGHTS Demonstration of infection of game birds with Pigeon paramyxovirus-1 (PPMV-1).There are differing dynamics of infection between different game bird species.Differing dynamics of infection between different PPMV-1 isolates and genotypes in game birds and chickens.

Novel equi merozoite antigen (ema-1) gene heterogeneity in a geographically isolated Theileria equi population in Croatia.

BACKGROUND: The apicomplexan haemoparasite Theileria equi, a causative agent of equine piroplasmosis, is an established pathogen of significant welfare and economic concern within the Croatian equine population. A previous large surveillance study of T. equi has identified two distinct parasite populations, one in the north and one in the south, geographically separated by the Dinaric Alps, which traverse the country. This study aimed to further investigate the genetic diversity within these two populations, focussing on allelic variability of the equi merozoite antigen gene, ema-1. METHODS: Following nested PCR of DNA isolates, the generated ema-1 amplicons were subsequently sequenced and compared by phylogenetic analysis to available sequences representing previously described ema-1 genotypes (groups A-C). RESULTS: Isolates from the southern T. equi population clustered with the existing ema-1 groups A and B. Strikingly, isolates from the northern population clustered into two novel ema-1 genotypes, named groups D and E. CONCLUSIONS: This detection of hitherto unreported genotypes suggests that historic geographical isolation has led to a degree of divergent evolution in this northern T. equi population. Additionally, current global regulatory testing of equine piroplasmosis relies heavily on EMA-1 based immunodiagnostics, and the discovery of unique ema-1 genotypes may question the efficacy of current diagnostics in international equine movement, with ramifications for the global equine community.

Imeglimin in type 2 diabetes.

Type 2 diabetes mellitus is a chronic disease most often characterized by increased glucose levels. When blood glucose levels are inadequately controlled or left untreated, the result is a variety of microvascular and macrovascular complications. To prevent these outcomes, many medications are available to manage type 2 diabetes mellitus and prevent disease progression. However, most of the medications available to date only target a few of the physiological defects caused by diabetes and may come with side effects that make adherence to the medication improbable. Imeglimin, a medication currently under investigation in the United States and approved in Japan, is a novel, first-in-its-class medication with a mechanism that is currently understood to target multiple pathways to provide glycemic control. This review aims to present and discuss the current clinical and scientific evidence pertaining to imeglimin.

A study comparing the healthy and diseased equine glandular gastric microbiota sampled with sheathed transendoscopic cytology brushes.

The role of the equine gastrointestinal microbiota in the pathogenesis of equine glandular gastric disease (EGGD) is poorly understood. To investigate whether the glandular gastric microbiota is altered in horses with EGGD. Prospective longitudinal study. Five Thoroughbred racehorses from one training center underwent gastroscopy as part of poor performance investigation. Samples were taken from EGGD lesions and adjacent normal mucosa using sheathed transendoscopic cytology brushes and frozen at -80°C. DNA was extracted for 16S rRNA sequencing, and sequences compared against a database to generate taxonomic classification of the microbiota. The same horses were sampled 6 months later. Normal glandular mucosal samples were characterized by a higher proportion of Proteobacteria (46.3%) than EGGD lesions (18.9%). Relative abundance of Firmicutes was lower in samples from normal mucosa (20.0%) than EGGD lesions (41.2%). Linear discriminant analysis effect size (LEfSe) confirmed a greater proportion of Firmicutes species was characteristic of samples collected from EGGD lesions due to a very high relative abundance of Sarcina (up to 92.4%) in two horses with EGGD. We were unable to comment on the stability of the glandular gastric microbiota over time. Small sample population. None of the horses examined had grossly normal gastric mucosa. The gastric microbiota appears altered in EGGD, although we are unable to demonstrate a causative effect. Sarcina was particularly increased in abundance in EGGD and may be a useful biomarker of disease. Sheathed cytology brushes were an effective method for sampling the gastric mucosa.

Clinical outcomes and the impact of prior oral anticoagulant use in patients with coronavirus disease 2019 admitted to hospitals in the UK - a multicentre observational study.

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease 2019 (COVID-19). Patients on oral anticoagulants (OAC) prior to diagnosis of COVID-19 may therefore have better outcomes. In this multicentre observational study of 5 883 patients (≥18 years) admitted to 26 UK hospitals between 1 April 2020 and 31 July 2020, overall mortality was 29·2%. Incidences of thrombosis, major bleeding (MB) and multiorgan failure (MOF) were 5·4%, 1·7% and 3·3% respectively. The presence of thrombosis, MB, or MOF was associated with a 1·8, 4·5 or 5·9-fold increased risk of dying, respectively. Of the 5 883 patients studied, 83·6% (n = 4 920) were not on OAC and 16·4% (n = 963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis [hazard ratio (HR) 1·05, 95% confidence interval (CI) 0·93-1·19; P = 0·15] or in an adjusted propensity score analysis (HR 0·92 95% CI 0·58-1·450; P = 0·18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulation prior to diagnosis of COVID-19 was admission to the Intensive-Care Unit (ICU) (HR 1·98, 95% CI 1·37-2·85). Thrombosis, MB, and MOF were associated with higher mortality. Our results indicate that patients may have benefit from prior OAC use, especially reduced admission to ICU, without any increase in bleeding.

A Review on the Efficacy and Safety of Oral Semaglutide.

There are numerous treatment options currently available for patients with type 2 diabetes mellitus; however, a multitude of patients continue to have inadequately controlled glycemic levels with their current antihyperglycemic regimen. Furthermore, the American Diabetes Association guidelines increasingly highlight the importance of multifactorial management and optimizing medication regimens that include cardiovascular, renal, and/or weight benefits in patients with type 2 diabetes mellitus. Glucagon-like peptide-1 receptor agonists belong to a novel class of type 2 diabetes mellitus agents that are becoming increasingly prevalent owing to their ability to improve glycemic status without the risk of hypoglycemia. Currently, there are three US Food and Drug Administration-approved glucagon-like peptide-1 receptor agonists, subcutaneous semaglutide, dulaglutide, and liraglutide, that also have an indication for reducing major adverse cardiovascular events in patients with type 2 diabetes mellitus and established cardiovascular disease. However, these agents are not often the first options because of their subcutaneous administration. Nevertheless, co-formulation of oral semaglutide with an absorption enhancer has shown to increase its bioavailability and has made its oral absorption possible. In the PIONEER trials, oral semaglutide effectively lowered blood glucose levels, and showed benefits on weight and cardiovascular outcomes; however, there is no Food and Drug Administration indication approved yet as the SOUL trial is still ongoing. Such characteristics of oral semaglutide may improve and increase its use compared to subcutaneous agents and possibly lead to earlier cardiovascular protection in addition to achieving glycemic control.

First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models.

BACKGROUND: MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. METHODS: Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. RESULTS: ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. CONCLUSION: The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.