In silico transcriptome screens identify epidermal growth factor receptor inhibitors as therapeutics for noise-induced hearing loss.

Noise-induced hearing loss (NIHL) is a common sensorineural hearing impairment that lacks U.S. Food and Drug Administration-approved drugs. To fill the gap in effective screening models, we used an in silico transcriptome-based drug screening approach, identifying 22 biological pathways and 64 potential small molecule treatments for NIHL. Two of these, afatinib and zorifertinib [epidermal growth factor receptor (EGFR) inhibitors], showed efficacy in zebrafish and mouse models. Further tests with EGFR knockout mice and EGF-morpholino zebrafish confirmed their protective role against NIHL. Molecular studies in mice highlighted EGFR's crucial involvement in NIHL and the protective effect of zorifertinib. When given orally, zorifertinib was found in the perilymph with favorable pharmacokinetics. In addition, zorifertinib combined with AZD5438 (a cyclin-dependent kinase 2 inhibitor) synergistically prevented NIHL in zebrafish. Our results underscore the potential for in silico transcriptome-based drug screening in diseases lacking efficient models and suggest EGFR inhibitors as potential treatments for NIHL, meriting clinical trials.

Antipsychotics impair regulation of glucose metabolism by central glucose.

Hypothalamic detection of elevated circulating glucose triggers suppression of endogenous glucose production (EGP) to maintain glucose homeostasis. Antipsychotics alleviate symptoms associated with schizophrenia but also increase the risk for impaired glucose metabolism. In the current study, we examined whether two acutely administered antipsychotics from different drug classes, haloperidol (first generation antipsychotic) and olanzapine (second generation antipsychotic), affect the ability of intracerebroventricular (ICV) glucose infusion approximating postprandial levels to suppress EGP. The experimental protocol consisted of a pancreatic euglycemic clamp, followed by kinomic and RNA-seq analyses of hypothalamic samples to determine changes in serine/threonine kinase activity and gene expression, respectively. Both antipsychotics inhibited ICV glucose-mediated increases in glucose infusion rate during the clamp, a measure of whole-body glucose metabolism. Similarly, olanzapine and haloperidol blocked central glucose-induced suppression of EGP. ICV glucose stimulated the vascular endothelial growth factor (VEGF) pathway, phosphatidylinositol 3-kinase (PI3K) pathway, and kinases capable of activating KATP channels in the hypothalamus. These effects were inhibited by both antipsychotics. In conclusion, olanzapine and haloperidol impair central glucose sensing. Although results of hypothalamic analyses in our study do not prove causality, they are novel and provide the basis for a multitude of future studies.

Variability in non-core vaccination rates of dogs and cats in veterinary clinics across the United States.

Vaccination guidelines for dogs and cats indicate that core vaccines (for dogs, rabies, distemper, adenovirus, parvovirus; for cats, feline parvovirus, herpes virus-1, calicivirus) are essential to maintain health, and that non-core vaccines be administered according to a clinician's assessment of a pet's risk of exposure and susceptibility to infection. A reliance on individual risk assessment introduces the potential for between-practice inconsistencies in non-core vaccine recommendations. A study was initiated to determine non-core vaccination rates of dogs (Leptospira, Borrelia burgdorferi, Bordetella bronchiseptica, canine influenza virus) and cats (feline leukemia virus) in patients current for core vaccines in veterinary practices across the United States. Transactional data for 5,531,866 dogs (1,670 practices) and 1,914,373 cats (1,661 practices) were retrieved from practice management systems for the period November 1, 2016 through January 1, 2020, deidentified and normalized. Non-core vaccination status was evaluated in 2,798,875 dogs and 788,772 cats that were core-vaccine current. Nationally, median clinic vaccination rates for dogs were highest for leptospirosis (70.5%) and B. bronchiseptica (68.7%), and much lower for canine influenza (4.8%). In Lyme-endemic states, the median clinic borreliosis vaccination rate was 51.8%. Feline leukemia median clinic vaccination rates were low for adult cats (34.6%) and for kittens and 1-year old cats (36.8%). Individual clinic vaccination rates ranged from 0 to 100% for leptospirosis, B. bronchiseptica and feline leukemia, 0-96% for canine influenza, and 0-94% for borreliosis. Wide variation in non-core vaccination rates between clinics in similar geographies indicates that factors other than disease risk are driving the use of non-core vaccines in pet dogs and cats, highlighting a need for veterinary practices to address gaps in patient protection. Failure to implement effective non-core vaccination strategies leaves susceptible dogs and cats unprotected against vaccine-preventable diseases.

Computer assisted versus conventional total knee replacement: a comparison of tourniquet time, blood loss and length of stay.

UNLABELLED: AIMS AND INTRODUCTION: The aim of this study was to assess whether navigated total knee arthroplasty (TKA) reduces peri-operative blood loss and post-operative length of stay when compared to conventional total knee arthroplasty techniques. PATIENTS AND METHODS: A retrospective case-note review of 143 patients undergoing primary elective total knee arthroplasty was carried out. Two surgeons in this institution perform conventional knee arthroplasty using intramedullary alignment with another two surgeons using the computer assisted technique. Blood losses were calculated using the Meunier et al. (2008) [23] method for calculation of peri-operative blood loss. This is based on changes in peri-operative blood indices compared to the patient's theoretical total blood volume which is calculated using the patient's pre-operative height and weight. Tourniquet time and post-operative length of stay for the two techniques of arthroplasty were also recorded. RESULTS: Sixty eight patients underwent conventional TKA and 75 patients had navigated TKA's performed. This data showed no significant difference in blood loss (p=0.56) or post-operative length of stay (p=0.36). A significant difference in tourniquet time between the two techniques was demonstrated (p=0.01). CONCLUSION: In this study there was no significant reduction in post-operative length of stay and peri-operative blood loss when using computer-assisted techniques. There was an increase in tourniquet time with the computer-assisted technique that may have implications upon work productivity for primary cemented knee arthroplasty.

Does the Lachman testing method affect the reliability of the International Knee Documentation Committee (IKDC) Form?

The aim of this study was to evaluate the effect of manual and instrumented means of Lachman testing on the reliability of the IKDC form. A single observer assessed 102 patients with ACL deficiency (direct comparison group). Another observer assessed 35 of these patients (inter-observer group) and the initial observer re-assessed 47 patients (test-retest group). The Lachman test was performed by both manual and instrumented means and the IKDC form was completed. Direct comparison of the manual and instrumented Lachman test revealed satisfactory levels for use. Further comparison revealed satisfactory test re-test and unsatisfactory inter-observer reliability for both means. On application into the IKDC form, direct comparison of both means of testing revealed satisfactory agreement for the overall score, but not the ligament group or Lachman item scores. Test-retest and inter-observer reliability testing revealed unsatisfactory agreement for the overall, ligament group and Lachman item scores for both means of testing. When using the IKDC form we recommend that a single observer perform the Lachman test by manual means on each occasion. If the original IKDC form is used only the overall score should be presented. Where the new IKDC form is used we recommend caution in the presentation of the examination section. We call into question the usefulness of the original IKDC form and the examination section of the new IKDC form in clinical research.