Vocalizations of the Pekin duck (Anas platyrhynchos domesticus): how stimuli, sex, and social groups affect their vocal repertoire.

Pekin ducks are exposed to stressors such as heat stress, enteric pathogens, mycotoxins, and other environmental stressors. We know from wild bird literature that birds communicate through vocalizations. We hypothesized that Pekin ducks would have a diverse repertoire that is affected by the sex, social group, and specific stimuli. We utilized adult Pekin ducks to develop a vocal repertoire. We placed 1 to 4 ducks of varying sexes into a sound chamber with various stimuli used to encourage new vocalizations. Birds were recorded for 20 min with several variations of number and sexes of ducks. Once the ducks were recorded each vocalization that was clipped was named based on a predetermined naming system. We characterized the vocal system of the ducks under each stimulus and social treatment in 4 ways: overall call rates, call diversity, call repertoire, and call spectral properties. In all cases, normality of residuals and homogeneity of variances for GLM and ANOVA models were confirmed using Proc Univariate (SAS v9.4) where a p ≤ 0.05 was considered significant. We found that Pekin ducks produce up to 16 different vocalizations. The treatments had a significant effect on the overall rate of calls given by the ducks (ANOVA: F6,31 = 8.55, p < 0.0001). Ducks produced the most calls by far when someone was sitting in the chamber with them (30.04 ± 4.45 calls/min). For call diversity, we found that there was a significant main effect of hen number (F218 = 12.21, p = 0.0004) but no main effect of drake number (F3,18 = 3.04, p = 0.0555). Cluster analyses indicated that certain types of calls were given under specific conditions. There were generally 6 major clusters of vocal repertoires (R-square = 0.899, Cubic Clustering Criterion = 9.30). Our results suggest that Pekin ducks are affected by the types of stimuli and social environment in how much they vocalize and in the properties of the calls they use. In addition, males and females differ somewhat in the repertoire of the calls they use, and in the spectral properties of their calls.

A rare case of an extra-oral plasmablastic lymphoma presenting through a scrotal abscess in a 42-year-old man.

Plasmablastic lymphoma (PBL) is a rare lymphoid neoplasm frequently presenting in the oral cavity. It is an aggressive type of non-Hodgkin's lymphoma that shares pathological features with plasma cell myeloma. In addition to human immunodeficiency virus (HIV), it is also associated with Epstein-Bar virus (EBV) and immunosuppression in HIV-negative patients, for example, post transplantation. Extra-oral PBL is rare and only a few case reports involving the testis have been described. Here we describe the first reported case of PBL presenting with a scrotal abscess (not involving the testes) in a patient newly diagnosed with HIV. This case highlights the rare presentation of a rare disease, the difficulties in establishing a diagnosis and the importance of a timely multidisciplinary approach to its management.

HER2-low expression in patients with advanced or metastatic solid tumors.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low is a newly defined category with HER2 1+ or 2+ expression by immunohistochemistry (IHC) and lack of HER2 gene amplification measured by in situ hybridization (ISH). Much remains unknown about the HER2-low status across tumor types and changes in HER2 status between primary and metastatic samples. PATIENTS AND METHODS: HER2 expression by IHC was evaluated in 4701 patients with solid tumors. We have evaluated the HER2 expression by IHC and amplification by ISH in paired breast and gastric/gastroesophageal (GEJ) primary and metastatic samples. HER2 expression was correlated with ERBB2 genomic alterations evaluated by next-generation sequencing (NGS) in non-breast, non-gastric/GEJ samples. RESULTS: HER2 expression (HER2 IHC 1-3+) was found in half (49.8%) of the cancers, with HER2-low (1 or 2+) found in many tumor types: 47.1% in breast, 34.6% in gastric/GEJ, 50.0% in salivary gland, 46.9% in lung, 46.5% in endometrial, 46% in urothelial, and 45.5% of gallbladder cancers. The concordance evaluation of HER2 expression between primary and metastatic breast cancer samples showed that HER2 3+ remained unchanged in 87.1% with a strong agreement between primary and metastatic samples, with a weighted kappa (Κ) of 0.85 (95% confidence interval 0.79-0.91). ERBB2 alterations were identified in 117 (7.5%) patients with non-breast, non-gastric/GEJ solid tumors who had NGS testing. Of 1436 patients without ERBB2 alterations, 512 (35.7%) showed any level HER2 expression by IHC. CONCLUSION: Our results show that HER2-low expression is frequently found across tumor types. These findings suggest that many patients with HER2-low solid tumors might benefit from HER2-targeted therapies.

Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Timing of dental extractions in patients undergoing radiotherapy and the incidence of osteoradionecrosis: a systematic review and meta-analysis.

This systematic review aimed to examine whether the incidence of osteonecrosis differed between patients who have dental extractions before or after radiotherapy (RT). The reported incidence of osteoradionecrosis (ORN) of the jaws following RT to the head and neck varies widely in the literature. Currently, for patients with head and neck cancer there are no universally accepted guidelines on the optimal timing of dental surgery relative to RT to minimise incident ORN. A literature review was conducted using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) criteria. A search of PubMed, EMBASE, Evidence-Based Medicine, and Web of Science databases targeted literature published up to and including 10 April 2020. Two independent reviewers assessed studies for eligibility against inclusion criteria. An assessment of bias was conducted for each of the included studies and relevant data extracted. A meta-analysis was undertaken using the statistical methods described. Twenty-four of 708 studies were included. They were heterogeneous and included a wide variation of RT methods, head and neck malignancies, and comorbidities. While some concluded that the incidence of ORN was dependent on the timing of dental extractions in relation to RT, with regard to the risk of its development, others reported additional factors such as age, comorbidities, extent of surgical resection, and dose and field of radiation, as more important predictors than timing. In many there was consistent lack of detail around the timing of dental procedures in relation to the delivery of RT. From 21 studies including 36,294 patients, of whom 14,389 had extractions before RT, the pooled incidence of ORN was 5.5% (95% CI: 2.1% to 10.1%). Significant heterogeneity was found in Cochran's Q-test (p<0.001) and Higgins I2=98.0%. From 21 studies including 37,805 patients, of whom 6030 had extractions after RT, the pooled incidence of ORN was 5.3% (95% CI: 2.9% to 8.2%). Significant heterogeneity was found in Cochran's Q-test (p<0.001) and Higgins I2=80.0%. There was no statistically significant difference between these two groups (random-effects model Q=0.12, p=0.73). Large, longitudinal studies with a priori-specified methods are needed to identify, recruit, and prospectively follow patients with head and neck cancer for the onset of ORN after dental surgery. This will allow clinical guidelines to be established to assist clinicians to plan treatment when extractions are indicated in patients undergoing RT to the head and neck.

Acute kidney injury following endovascular intervention for peripheral artery disease.

BACKGROUND: The incidence of, and risk factors for, acute kidney injury (AKI) after endovascular intervention for peripheral artery disease (PAD) remain unknown. The aim of this study was to assess the proportion of patients who develop AKI and explore the risk factors. METHODS: Prospectively collected data on patients undergoing femoropopliteal endovascular intervention for symptomatic PAD across three vascular centres were analysed. The proportion of patients developing AKI (according to the Kidney Disease Improving Global Outcomes definition) within 48 h, and the proportion developing the composite Major Adverse Kidney Events (MAKE) endpoints (death, dialysis, drop in estimated glomerular filtration rate at least 25 per cent) at 30 days (MAKE30) and remains 90 days (MAKE90) were calculated. Multivariable regression analysis was used to assess predictors of AKI, and the association between AKI and death. RESULTS: Some 2041 patients were included in the analysis. AKI developed in 239 patients (11.7 per cent), with 47 (2.3 per cent) requiring dialysis within 30 days, and 18 (0.9 per cent) requiring ongoing dialysis. The MAKE30 and MAKE90 composite endpoints were reached in 358 (17.5 per cent) and 449 (22.0 per cent) patients respectively. Risk factors for AKI were age, sex, congestive heart failure, chronic limb-threatening ischaemia, emergency procedure, and pre-existing chronic kidney disease. AKI, dementia, congestive heart failure, and major amputation were risk factors for medium-term mortality. CONCLUSION: AKI is a common complication after intervention for PAD and is associated with medium-term mortality.

Non-invasive screening of a microRNA-based dysregulation signature in oral cancer and oral potentially malignant disorders.

INTRODUCTION: We have previously shown that oral swirls are a robust source of microRNA protected by extracellular vesicles, potentially useful to detect oral squamous cell carcinoma (OSCC)-associated molecular aberration. OBJECTIVES: To study a developed dysregulation score and risk classification algorithm based upon a panel of OSCC-associated microRNA in oral swirls from individuals with OSCC and oral potentially malignant disorders (OPMDs). MATERIALS AND METHODS: An OSCC-associated panel of 5 microRNAs (miR-24; miR-21; miR-99a; let-7c; miR-100;) was quantified by qPCR in 190 individuals with and without mucosal abnormalities, including OSCC (n = 53) and OPMDs (n = 74). Each sample was analyzed using a developed dysregulation score (dSCORE) and risk classification algorithm, allocating a LOW- or HIGH-RISK score. The influence of demographic, systemic, oral health and mucosal disease factors on the developed test was analyzed. RESULTS: MicroRNA for analysis can be predictably isolated from oral swirls sourced from individuals with a range of demographic, systemic and oral health findings. Utilizing the presence of HIGH-RISK identified OSCC patients with 86.8% sensitivity and 81.5% specificity. Older age and female gender were associated with higher dSCOREs and higher proportions of HIGH-RISK classification amongst individuals with no mucosal abnormalities. The dSCOREs for all subgroups of OPMDs were significantly different from the OSCC group. CONCLUSION: This is the first comparison of microRNA sourced from oral swirls from individuals with OPMDs with individuals with and without OSCC. A HIGH-RISK dysregulation signature was found to be accurate in indicating the presence of OSCC and exampled to parallel malignant transformation.

Oral swirl samples - a robust source of microRNA protected by extracellular vesicles.

BACKGROUND: MicroRNAs are small non-coding RNAs which are dysregulated in disease states, such as oral cancer. Extracellular vesicles, a potential source of microRNA, are found in saliva. OBJECTIVE: To demonstrate that a quantifiable amount of microRNA can be isolated from oral swirl samples. Additionally, we hypothesized that extracellular vesicles may protect contained microRNA from degradation in these samples. METHOD: A polyethylene glycol-based precipitation was used for extracellular vesicle enrichment of oral swirl samples. Comparison was made between samples treated with and without RNase. Further, samples from three subjects were exposed to a range of conditions over 7 days and assessed for presence of microRNA by reverse-transcription quantitative PCR. Extracellular vesicles from samples were identified under transmission electron microscopy. RESULTS: An adequate quantity of microRNA for qPCR analysis was extractable from samples despite exposure to conditions under which degradation of RNA would be expected. CONCLUSION: A technique was developed to isolate an adequate quantity of microRNA for analysis from oral swirl samples. Extracellular vesicle-associated microRNA may be protected from degradation. This technique moves towards chairside application of translational microRNA research in the field of oral cancer prognostics.

Mechanism and non-mechanism based imaging biomarkers for assessing biological response to treatment in non-small cell lung cancer.

Therapeutic options in locally advanced non-small cell lung cancer (NSCLC) have expanded in the past decade to include a palate of targeted interventions such as high dose targeted thermal ablations, radiotherapy and growing platform of antibody and small molecule therapies and immunotherapies. Although these therapies have varied mechanisms of action, they often induce changes in tumour architecture and microenvironment such that response is not always accompanied by early reduction in tumour mass, and evaluation by criteria other than size is needed to report more effectively on response. Functional imaging techniques, which probe the tumour and its microenvironment through novel positron emission tomography and magnetic resonance imaging techniques, offer more detailed insights into and quantitation of tumour response than is available on anatomical imaging alone. Use of these biomarkers, or other rational combinations as readouts of pathological response in NSCLC have potential to provide more accurate predictors of treatment outcomes. In this article, the robustness of the more commonly available positron emission tomography and magnetic resonance imaging biomarker indices is examined and the evidence for their application in NSCLC is reviewed.

The accuracy of the Edinburgh diplopia diagnostic algorithm.

PurposeTo assess the diagnostic accuracy of the Edinburgh diplopia diagnostic algorithm.MethodsThis was a prospective study. Details of consecutive patients referred to ophthalmology clinics at Falkirk Community Hospital and Princess Alexandra Eye Pavilion, Edinburgh, with double vision were collected by the clinician first seeing the patient and passed to the investigators. The investigators then assessed the patient using the algorithm. An assessment of the degree of concordance between the 'algorithm assisted' diagnosis and the 'gold standard' diagnosis, made by a consultant ophthalmologist was then carried out. The accuracy of the pre-algorithm diagnosis made by the referrer was also noted.ResultsAll patients referred with diplopia were eligible for inclusion. Fifty-one patients were assessed; six were excluded. The pre-algorithm accuracy of referrers was 24% (10/41). The algorithm assisted diagnosis was correct 82% (37/45) of the time. It correctly diagnosed: cranial nerve (CN) III palsy in 6/6, CN IV palsy in 7/8, CN VI palsy in 12/12, internuclear ophthalmoplegia in 4/4, restrictive myopathy in 4/4, media opacity in 1/1, and blurred vision in 3/3. The algorithm assisted diagnosis was wrong in 18% (8/45) of the patients.ConclusionsThe baseline diagnostic accuracy of non-ophthalmologists rose from 24 to 82% when patients were assessed using the algorithm. The improvement in the diagnostic accuracy resulting from the use of the algorithm would, hopefully, result in more accurate triage of patients with diplopia that are referred to the hospital eye service. We hope we have demonstrated its potential as a learning tool for inexperienced clinicians.

Phase I trial outcomes in older patients with advanced solid tumours.

BACKGROUND: This study had two aims: (a) to test the hypothesis that advanced age is associated with lower levels of tolerability and clinical benefit to experimental Phase I trial agents; (b) to assess the validity of the Royal Marsden Hospital (RMH) prognostic score as a patient selection tool in older patients. METHODS: Clinico-pathological characteristics and treatment outcomes of all patients treated consecutively from 2005 to 2009 in phase I trials at the RMH were recorded. All toxicity and clinical outcome data were compared between patients aged below and above 65 years of age. RESULTS: One thousand and four patients were treated in 30 Phase I trials, with 315 (31%) patients aged 65 years and older. Grade 3-5 toxicities (22.8% vs 24.8% (P=0.52)), trial discontinuation (6% vs 4%; P=0.33), and dose interruptions (8.0% vs 8.0% (P=0.96)) were observed at similar rates in patients below and above 65 years of age, respectively. The overall response rate 5.2% vs 4.1%, progression-free survival (PFS) 1.9 vs 3.5 months and clinical benefit rate (CBR) at 6 months 15.2% vs 14.3% were comparable in both groups. To avoid bias due to the potential therapeutic benefit of abiraterone, comparisons were repeated excluding prostate cancer patients with similar results (ORR 4.6% vs 4%, PFS 1.8 vs 3.0 months, CBR at 6 months 13.5% vs 9.5%). Multivariate analysis indicated that the previously identified RMH score (including albumin and lactate dehydrogenase levels) was an accurate predictor of outcome. CONCLUSIONS: Phase I clinical trials should be considered in patients with advanced cancers regardless of age, as older patients who enter these have similar safety and efficacy outcomes as their younger counterparts. The RMH prognostic score can assist in the selection of suitable older patients.

Methoxyflurane: a review with emphasis on its role in dental practice.

Methoxyflurane was developed as an anaesthetic agent and introduced into clinical practice in 1960. It soon became evident that it possessed analgesic properties that other drugs did not. Due to toxicity concerns, it lost favour in general anaesthesia and had been largely abandoned by the late 1970s. The manufacturer withdrew it in 1999, and the Food and Drug Administration in the United States did not renew its licence in 2005. It has also been withdrawn by the European Union. However, it continues to be used in Australasia, primarily as an inhaled self-administered analgesic by emergency services immediately following trauma. It has become attractive for use in dental practice, likely due to its effectiveness as an analgesic and its additional sedative qualities. Its acceptance is controversial as its use in dentistry is largely elective. Despite its good safety record in analgesic doses, adverse reactions have been recorded. Practitioners should be well aware of risks associated with its use before considering administration, and carefully assess whether or not there are equally good alternative options that do not the carry the same risks. Methoxyflurane is reviewed below with an emphasis on its use in dental practice.

Oral candidal carriage in asymptomatic patients.

BACKGROUND: Interest in the association between oral cancer risk and Candida-associated promotion of mucosal dysplasia continues. However, little is known of the presence and amount of oral yeast in the mouths of healthy patients without mucosal lesions. The purpose of this prospective cross-sectional clinical study was to ascertain the prevalence and degree of carriage of Candida in the oral cavities of a non-cancer population, with reference to a range of parameters affecting the oral environment. METHODS: Oral rinse samples were collected from a sample of 203 patients attending the Royal Dental Hospital of Melbourne and analysed for the presence and degree of colonization of yeast species that were phenotypically identified as albicans and non-albicans species. RESULTS: Oral yeast carriage was found in 98/203 patients (48.3%), and of these, 83 (84.7%) patients carried C. albicans. There was no statistical difference in carriage when comparing gender, age, or presence of a removable prosthesis. CONCLUSIONS: Both smoking and the presence of active carious lesions were found to be positively correlated with the carriage of oral Candida. Individuals who are current smokers are nearly seven times more likely to have oral Candida, and participants with high candidal colonization are more likely to be current smokers. Participants with active carious lesions were also more likely to carry oral Candida.

Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials.

BACKGROUND: PI3K-AKT-mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. METHODS: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. RESULTS: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3-4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3-4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. CONCLUSIONS: PI3K-AKT-mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.

Oral medicine and the ageing population.

The oral cavity is subject to age related processes such as cellular ageing and immunosenescence. The ageing population bears an increased burden of intraoral pathology. In oral medicine, the majority of presenting patients are in their fifth to seventh decade of life. In this review, we discuss the ageing population's susceptibility to mucosal disorders and the increased prevalence of potentially malignant disorders and oral squamous cell carcinoma, as well as dermatoses including oral lichen planus and immunobullous conditions. We also address the ageing population's susceptibility to oral discomfort and explore salivary secretion, ulceration and the symptoms of oral burning. Finally, we will describe orofacial pain conditions which are more likely encountered in an older population. This update highlights clinical presentations which are more likely to be encountered in the ageing population in a general practice setting and the importance of screening both new and long-term patients.