Strategies for senolytic drug discovery.

Senolytics are a category of drugs that reduce the impact of cellular senescence, an effect associated with a range of chronic and age-related diseases. Since the discovery of the first senolytics in 2015, the number of known senolytic agents has grown dramatically. This review discusses the broad categories of known senolytics-kinase inhibitors, Bcl-2 family protein inhibitors, naturally occurring polyphenols, heat shock protein inhibitors, BET family protein inhibitors, P53 stabilizers, repurposed anti-cancer drugs, cardiac steroids, PPAR-alpha agonists, and antibiotics. The approaches used to screen for new senolytics are articulated including a range of methods to induce senescence, different target cell types, various senolytic assays, and markers. The choice of methods can greatly influence the outcomes of a screen, with high-quality screens featuring robust systems, adequate controls, and extensive validation in alternate assays. Recent advances in single-cell analysis and computational methods for senolytic identification are also discussed. There is significant potential for further drug discovery, but this will require additional research into drug targets and mechanisms of actions and their subsequent rigorous evaluation in pre-clinical models and human trials.

The positives, the challenges and the impact; an exploration of early career nurses experiences in the Emergency Department.

BACKGROUND: The intense working environment of the Emergency Department (ED) is exciting and rewarding; but is renowned for high staff turnover and burnout. The wellbeing and retention of the existing workforce is imperative. The purpose of this study was to explore the experiences of early careers nurses in the ED; identify aspects of ED they enjoyed, the challenges and explore potential coping mechanisms used to mitigate negative situations. METHODS: A qualitative design was used. Eleven semi-structured interviews were conducted with adult and paediatric emergency nurses who had worked in the ED for less than three years. Data were transcribed, open coded and analysed using thematic analysis. RESULTS: Four key themes emerged; (1) Drawn to emergency nursing; (2) Teamwork; (3) Time to care; and (4) Reflections on the impact. CONCLUSION: Opportunities for learning and development and being able to provide good levels of patient care were identified important to participants. Challenging aspects of the job included high workloads, exposure to traumatic incidents, violence and aggression. The psychological impact included feelings of burnout, exhaustion, flashbacks, personal growth and perspective. Teamwork, a strong support network and opportunities for formal and informal debrief were identified as helping to mitigate challenging aspects of the job.

Identifying HSV-1 Inhibitors from Natural Compounds via Virtual Screening Targeting Surface Glycoprotein D.

Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could interact synergistically with first-line antiherpetic agents to accelerate the resolution of HSV-1-associated lesions. For this study, we applied a structure-based molecular docking approach targeting the nectin-1 and herpesvirus entry mediator (HVEM) binding interfaces of the viral glycoprotein D (gD). More than 527,000 natural compounds were virtually screened using Autodock Vina and then filtered for favorable ADMET profiles. Eight top hits were evaluated experimentally in African green monkey kidney cell line (VERO) cells, which yielded two compounds with potential antiherpetic activity. One active compound (1-(1-benzofuran-2-yl)-2-[(5Z)-2H,6H,7H,8H-[1,3] dioxolo[4,5-g]isoquinoline-5-ylidene]ethenone) showed weak but significant antiviral activity. Although less potent than antiherpetic agents, such as acyclovir, it acted at the viral inactivation stage in a dose-dependent manner, suggesting a novel mode of action. These results highlight the feasibility of in silico approaches for identifying new antiviral compounds, which may be further optimized by medicinal chemistry approaches.

Virtual screening and in vitro validation of natural compound inhibitors against SARS-CoV-2 spike protein.

The COVID-19 pandemic caused by the SARS-CoV-2 virus has led to a major public health burden and has resulted in millions of deaths worldwide. As effective treatments are limited, there is a significant requirement for high-throughput, low resource methods for the discovery of novel antivirals. The SARS-CoV-2 spike protein plays a key role in viral entry and has been identified as a therapeutic target. Using the available spike crystal structure, we performed a virtual screen with a library of 527 209 natural compounds against the receptor binding domain of this protein. Top hits from this screen were subjected to a second, more comprehensive molecular docking experiment and filtered for favourable ADMET properties. The in vitro activity of 10 highly ranked compounds was assessed using a virus neutralisation assay designed to facilitate viral entry in a physiologically relevant manner via the plasma membrane route. Subsequently, four compounds ZINC02111387, ZINC02122196, SN00074072 and ZINC04090608 were identified to possess antiviral activity in the µM range. These findings validate the virtual screening method as a tool for identifying novel antivirals and provide a basis for future drug development against SARS-CoV-2.

Predatory Publishing: How to Safely Navigate the Waters of Open Access.

Open access publishing enables scholarship to be openly accessible to everyone, which has countless benefits. However, the open access movement has opened the door for "predatory publishers" to take advantage of researchers surviving in this publish or perish academic landscape. Predatory journals are becoming increasingly common. Nursing researchers, instructors, and students need to be made aware of the dangers of predatory journals, and they need to know how to identify them. While there are blacklists and whitelists that can be used to aid in decision-making, it is critical to note that these lists can never be entirely up to date. This article incorporates a literature review which provides insights into newer trends in predatory and unethical publishing, including "journal hijacking" and "bogus impact factors". Extensive criteria for assessing emerging or unknown journals is compiled to aid researchers, students, educators, and the public in evaluating open access publications.

Abnormal sebaceous gland differentiation in 10 kittens ('sebaceous gland dysplasia') associated with generalized hypotrichosis and scaling.

A rare congenital dermatosis, characterized by progressive hypotrichosis with variable scaling and crusting, occurred in 10 short-haired kittens in North America and Europe. Lesions appeared at between 4 and 12 weeks of age, commencing on the head and becoming generalized. The tail was spared in two kittens. Generalized scaling was mild to moderate, often with prominent follicular casts. Periocular, perioral, pinnal and ear canal crusting was occasionally severe. The skin was thick and wrinkled in two kittens. Histologically, the main lesion was abnormal sebaceous gland morphology. Instead of regular differentiation from basal cells to mature sebocytes, the glands were composed of a haphazard collection of undifferentiated basaloid cells, some partly vacuolated and a few containing eosinophilic globules. Mitotic figures and apoptotic cells were present in an irregularly thickened follicular isthmus. Lymphocytic mural folliculitis and mild sebaceous adenitis were rare. Orthokeratotic hyperkeratosis and follicular casts were present. Hair follicles were of normal density and were mostly in anagen, but some contained malacic hair shafts. Perforating folliculitis, leading to dermal trichogranuloma formation, occurred occasionally. Further biopsy samples taken at 2 years and at 3 and 4 years, respectively, from two kittens revealed similar but often more severe sebaceous gland lesions. Hair follicles were smaller, with many in telogen. The young age of onset suggests a genetic defect interfering with sebaceous and, possibly, follicular development. These lesions are discussed with reference to studies of mouse mutants in which genetic defects in sebaceous differentiation cause a similar phenotype of hyperkeratosis and progressive alopecia.

Neonatal brachial plexus injury: comparison of incidence and antecedents between 2 decades.

OBJECTIVE: We sought to compare the incidence and antecedents of neonatal brachial plexus injury (BPI) in 2 different 5-year epochs a decade apart following the introduction of specific staff training in the management of shoulder dystocia. STUDY DESIGN: All infants with BPI were prospectively identified during 2004 through 2008. Injuries were correlated with maternal details and intrapartum events and compared with the earlier series. RESULTS: Of 41,828 deliveries during 2004 through 2008, 72 infants with BPI were identified (1.7/1000), compared to 54 cases (1.5/1000) from 1994 through 1998 (P = .4); 9 injuries (12.5%) were persistent from 2004 through 2008, compared with 10 (18.5%) earlier (P = .4). There were no significant differences between the 2 time periods with respect to maternal parity, obesity, or prolonged pregnancy, although the cesarean section rate had increased from 10.7 to 18.4%. CONCLUSION: Despite training in the management of shoulder dystocia and a rising institutional cesarean section rate, the incidence of BPI has remained unchanged compared with 10 years earlier.

Treatment of feline herpesvirus-1 associated disease in cats with famciclovir and related drugs.

BACKGROUND: Feline herpesvirus 1 (FHV-1) is a common cause of ocular and upper respiratory disease in cats and kittens, and a potential cause of eosinophilic dermatitis. HYPOTHESIS: The systemic anti-herpes drug, famciclovir (Famvir; Novartis), would be effective in the clinical management of disease attributable to FHV-1, including conjunctivitis, keratitis, corneal sequestra, rhinosinusitis and FHV-1 associated dermatitis. CLINICAL OUTCOME: Oral famciclovir was used to treat signs considered referable to FHV-1 in 10 cats: four had primary ocular disease, two had rhinosinusitis and four had FHV-1 associated dermatitis. Patients treated in Australia (five cats) and Europe (one cat) were given 62.5 mg of famciclovir once or twice daily. Four cats treated in the USA were given 125 mg three times daily. Famciclovir was uniformly well tolerated and, in all cases, had a positive impact on the patient's condition. The apparent improvement in lesions was superior to what had been achieved previously using other therapeutic strategies. One cat with severe destructive rhinosinusitis was significantly improved by a 4-month course of famciclovir in combination with antibacterials. Corneal sequestra detached in two out of three cats treated; cats with ocular signs were qualitatively more comfortable, with reduced clinical signs and an improved appearance of the eyes. Critically, oral famciclovir therapy was considered more convenient than topical ocular therapy. All four cats with FHV-1 associated dermatitis improved substantially, although relapse occurred subsequently in three patients. A further cat with presumptive FHV-1 associated dermatitis responded to topical aciclovir cream before famciclovir could be sourced. CONCLUSIONS: Famciclovir appears to be a promising systemic drug for treating diseases associated with FHV-1 infection. More rigorous clinical trials are required to optimise the dosing regimen for safe and effective specific anti-herpes treatment in feline clinical medicine.

Adverse effects of ketoconazole in dogs--a retrospective study.

Although ketoconazole has been used extensively in dogs for the treatment of various fungal infections, information about adverse effects is mainly anecdotal. Common adverse effects in humans include dose-dependant anorexia, nausea and vomiting, allergic rashes and pruritus. Drug-induced hepatitis is very rare, but potentially fatal. The aim of this study was to evaluate the type and frequency of adverse effects associated with ketoconazole therapy in dogs treated for skin diseases and any possible influence of dosage, duration of therapy, signalment or concurrent medication. The medical records of 632 dogs treated with ketoconazole (2.6-33.4 mg/kg) were reviewed. Adverse effects occurred in 14.6% (92 dogs) and included vomiting (7.1%), anorexia (4.9%), lethargy (1.9%), diarrhea (1.1%), pruritus (0.6%), erythema (0.3%) and other adverse effects (2.5%). Of the dogs with other adverse effects, four of 16 (25%) were ataxic and three of these received concurrent ivermectin. Adverse effects were significantly more often recorded in dogs concurrently treated with ciclosporin (P = 0.034) or ivermectin (P = 0.007). Increased liver enzyme levels were reported rarely, and icterus was not seen in any of the dogs. However, monitoring liver enzymes during therapy is recommended, although this might not necessarily prevent severe idiosyncratic hepatotoxicity.

Pemphigus foliaceus in 91 dogs.

A retrospective study of 91 dogs with pemphigus foliaceus was performed. Clinical signs of the disease included crusts (n=79), pustules (n=36), and alopecia (n=33). Lesions were most common on the trunk (n=53), inner pinnae (n=46), face (n=37), and foot pads (n=32). Cytological evaluation revealed acantholytic keratinocytes in 37 of 48 dogs. Results of combination treatment with prednisolone and azathioprine were comparable to results with prednisolone therapy alone. More than half of the dogs achieved remission with appropriate therapy, and another 25% significantly improved.

CCNU in the treatment of canine epitheliotropic lymphoma.

This retrospective study examined the use of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosurea) in 36 dogs with epitheliotropic lymphoma. Thirty-one (86%) dogs had the cutaneous form of disease, and 5 (14%) dogs had the oral form of disease. Nineteen (51%) dogs were treated with other chemotherapeutic agents before receiving CCNU. All dogs had detectable disease at the time CCNU therapy was initiated. Dogs received a median starting CCNU dosage of 70 mg/m2 (range, 50-100 mg/m2). The median number of treatments administered was 3 (range, 1-12 treatments). After the initial treatment, the CCNU dosage was adjusted in 9 of 26 (35%) dogs in which CCNU was continued: 7 had dosage reductions, and 2 had dosage escalations. Twenty-eight of 36 (78%) dogs had a measurable response to CCNU for a median duration of 106 days (95% confidence interval [CI], 75-182). Six dogs (17%) had a complete response, including 5 dogs with the cutaneous form and 1 dog with the oral form. Twenty-two dogs (61%) had a partial response, including 20 dogs with the cutaneous form and 2 dogs with the oral form, for a median duration of 88 days (95% CI, 62-170). Toxicoses after CCNU chemotherapy included myelosuppression in up to 29% of the dogs, gastrointestinal signs in up to 22% of the dogs, and liver enzyme activity increases in up to 86% of the dogs. This study demonstrates that CCNU chemotherapy can be considered a reasonable option for the treatment of canine epitheliotropic lymphoma in dogs.

Long-term use of cyclosporine in the treatment of canine atopic dermatitis.

This retrospective study of 51 dogs with atopic dermatitis (AD) treated with cyclosporine (CsA) for a minimum of 6 months assessed the frequency of dosing and the need for continual treatment to control clinical signs. The study evaluated both medical records and information supplied by the owners in the form of written questionnaires and telephone follow-up. Laboratory parameters, possible adverse effects and owner satisfaction were assessed. The dose of CsA was 5 mg/kg orally per day and dogs received CsA for 6-30 months. At the conclusion of the study period, 28 dogs (55%) needed ongoing CsA to control clinical signs of AD: 8 (15%) received CsA 2-3 days per week, 10 (20%) 4-5 days per week, and 10 (20%) daily. CsA was discontinued in 23 dogs (45%) after 6-24 months due to either a limited response (22%) or after achieving a clinical response (24%). The results suggest that some dogs with AD treated with CsA may not require daily or even ongoing treatment to control clinical signs. Laboratory abnormalities were detected in 13 dogs (25%) during their CsA treatment. Two dogs developed oral growths and three developed hirsuitism. Forty owners (78%) reported no adverse events in their dogs during the treatment period. Thirty-six owners (71%) were satisfied with CsA as treatment for their atopic dog.