Using simulation as a platform to prepare for ear, nose and throat emergencies in the coronavirus disease 2019 era and beyond.

BACKGROUND: Following limited clinical exposure during the coronavirus disease 2019 pandemic, a simulation-based platform aimed at providing a unique and safe learning tool was established. The aim was to improve the skills, knowledge and confidence of new ENT doctors. METHOD: The course was developed through 5 iterations over 28 months, moving from a half-day session to 2 full-day courses with more scenarios. Participant, faculty and local simulation team feedback drove course development. High-fidelity scenarios were provided, ranging from epistaxis to stridor, using technology including SimMan3 G mannequin, mask-Ed™ and nasendoscopy simulators. RESULTS: Participant feedback consistently demonstrated that the knowledge and skills acquired enhanced preparedness for working in ENT, with impact being sustained in clinical practice. CONCLUSION: Preparing healthcare professionals adequately is essential to enhancing patient safety. This simulation course has been effective in supporting new doctors in ENT and has subsequently been rolled out at a national level.

Analysis of the interactions between small pulmonary nodules, clinical factors and the risk of malignancy in the chest following diagnosis of head and neck cancer.

BACKGROUND: This study aims to investigate radiological and clinical factors which predict malignancy in indeterminate pulmonary nodules in patients with head and neck cancer (HNC). METHODS: Prospective data were collected in 424 patients who were reviewed in the NHS Lothian HNC multidisciplinary meeting from May 2016 to May 2018. Staging and follow-up CT chest imaging were reviewed to identify and assess pulmonary nodules in all patients. RESULTS: About 61.8% of patients had at least one pulmonary nodule at staging CT. In total, 25 patients developed malignancy in the chest. Metastatic disease in the chest was significantly associated with unknown or negative p16 status (p < .0005). Pleural indentation and spiculation were associated with indeterminate nodules, subsequently being shown to represent metastatic disease (p > .0005 and p = .046, respectively). CONCLUSION: Negative or unknown p16 status was associated with an increased propensity to develop metastatic disease in the chest in patients with HNC.

Case Report: The risks associated with chronic theophylline therapy and measures designed to improve monitoring and management.

BACKGROUND: Symptoms of theophylline toxicity and factors that augment the risk of developing it are well documented in the literature. However these appear to be poorly considered in clinical practice. This case underlines the challenges in recognising and managing theophylline toxicity; moreover the requirement for improved application of knowledge of its pharmacokinetics to our practice. CASE PRESENTATION: In this case we observe how theophylline toxicity can be overlooked due to the presence of non-specific symptoms and lack of a structured system to mitigate error in detection, in both hospital medicine and general practice. Here, the initial theophylline concentration measurement was documented as 59.3 mg/l in a patient taking the medication long-term, with the previous concentration being recorded one year prior. Management consisted of suspension of theophylline along with best supportive care, however in the process other conditions were exacerbated and the patient ultimately died in hospital. Congestive cardiac failure, congestive liver disease and polypharmacy were factors isolated from this case that expedited the patients' development of theophylline toxicity. This was perpetuated by delay in diagnosis due to presentation with generalised symptoms including tachycardia, vomiting and neurological symptoms. CONCLUSIONS: Findings from this case necessitate a requirement for more stringent monitoring of theophylline when taken chronically in those who demonstrate risk factors for toxicity. This would aim to prevent accumulation of the drug, toxicity onset and subsequent acute presentation to hospital. Intervention, through charcoal haemoperfusion may provide a means of enhanced recovery to reduce sequelae of toxicity.

Altered folate availability modifies the molecular environment of the human colorectum: implications for colorectal carcinogenesis.

Low folate status increases colorectal cancer risk. Paradoxically, overly abundant folate supplementation, which is not uncommon in the United States, may increase risk. The mechanisms of these effects are unknown. We conducted two translational studies to define molecular pathways in the human colon altered either by folate supplementation or by dietary folate depletion (followed by repletion). In the first study, 10 healthy, at-risk volunteers (with documented stable/normal folate intake) received supplemental folic acid (1 mg/d) for 8 weeks. In the second study, 10 similar subjects were admitted to a hospital as inpatients for 12 weeks to study folate depletion induced by a low folate diet. A repletion regimen of folic acid (1 mg/d) was provided for the last 4 of these weeks. Both studies included an 8-week run-in period to ensure stabilized folate levels prior to intervention. We obtained 12 rectosigmoid biopsies (from 4 quadrants of normal-appearing mucosa 10-15 cm from the anal verge) at baseline and at measured intervals in both studies for assessing the primary endpoints: genome-wide gene expression, genomic DNA methylation, promoter methylation (depletion/repletion study only), and p53 DNA strand breaks. Serum and rectosigmoid folate concentrations accurately tracked all changes in folate delivery (P < 0.05). In the first study, gene array analysis revealed that supplementation upregulated multiple inflammation- and immune-related pathways in addition to altering several 1-carbon-related enzymes (P < 0.001). In the second study, folate depletion downregulated genes involved in immune response, inflammation, the cell cycle, and mitochondrial/energy pathways; repletion reversed most of these changes. However, changes in gene expression after repletion in the second study (involving immune response and inflammation) did not reach the levels seen after supplementation in the first study. Neither genomic nor promoter-specific DNA methylation changed during the course of the depletion/repletion protocol, and genomic methylation did not change with supplementation in the first study. p53 DNA strand breaks increased with depletion after 12 weeks. In sum, depletion downregulates, whereas repletion or supplementation upregulates pathways related to inflammation and immune response. These findings provide novel support to the concept that excessive folate supplementation might promote colorectal carcinogenesis by enhancing proinflammatory and immune response pathways. These results indicate that modest changes in folate delivery create substantial changes in the molecular milieu of the human colon.

Effects of physical exercise on ADHD-like behavior in male and female adolescent spontaneously hypertensive rats.

The present study examined the effects of exercising (voluntary wheel running) during adolescence on attentional function in male and female spontaneously hypertensive rats (SHRs), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). Once rats reached adulthood, they received one session in which a light was presented 12 times but not reinforced, followed by training sessions in which the light was paired with a food reward. Male and female SHRs that had access to running wheels exhibited levels of unconditioned orienting behavior that were similar to Wistar-Kyoto rats (normo-active control) while SHRs that did not have access to running wheels exhibited higher levels of unconditioned orienting behavior. When the light was later paired with food there were no differences between the groups of male rats, but exercising female SHRs exhibited a decrease in conditioned food cup behavior. Consistent with their established phenotype, SHR rats exhibited more locomotor activity during an open field exploration session than WKY rats, but there was no relationship between orienting behavior and locomotor activity. Together these data suggest that physical exercise during adolescence can benefit attentional capabilities.

Interpreting the effects of exercise on fear conditioning: the influence of time of day.

Previous studies indicate that physical exercise improves contextual fear memory, as evidenced by increased freezing behavior when rats are returned to a training environment that was initially paired with footshock. However, freezing behavior could also be affected by fatigue, especially because rats were tested shortly after the end of the dark cycle, which is when most wheel running was likely to occur. In addition, exercise has been shown to have anxiolytic effects, further confounding interpretation of the effects of exercise on cognition when using aversive conditioning tasks. These factors were examined in the present study by comparing freezing behavior in exercising and nonexercising rats that were tested at different times in the light cycle. In addition, all rats were tested on an elevated plus maze to assess anxiety-like behavior and in an open-field apparatus to measure locomotor activity in order to directly examine interactions between freezing, anxiety-like behavior, and locomotion. Consistent with prior studies, exercising rats exhibited more context freezing than did sedentary rats when tested early in the light cycle. However, the opposite pattern of results was obtained when testing occurred late in the light cycle, an effect driven by a difference in the amount of freezing exhibited by the sedentary control groups. Indeed, the levels of context freezing exhibited by exercising rats were comparable regardless of when the rats were tested during the light cycle. These data have implications for interpreting the effects of exercise on aversive conditioning.

BDNF expression in perirhinal cortex is associated with exercise-induced improvement in object recognition memory.

Physical exercise induces widespread neurobiological adaptations and improves learning and memory. Most research in this field has focused on hippocampus-based spatial tasks and changes in brain-derived neurotrophic factor (BDNF) as a putative substrate underlying exercise-induced cognitive improvements. Chronic exercise can also be anxiolytic and causes adaptive changes in stress-reactivity. The present study employed a perirhinal cortex-dependent object recognition task as well as the elevated plus maze to directly test for interactions between the cognitive and anxiolytic effects of exercise in male Long Evans rats. Hippocampal and perirhinal cortex tissue was collected to determine whether the relationship between BDNF and cognitive performance extends to this non-spatial and non-hippocampal-dependent task. We also examined whether the cognitive improvements persisted once the exercise regimen was terminated. Our data indicate that 4weeks of voluntary exercise every-other-day improved object recognition memory. Importantly, BDNF expression in the perirhinal cortex of exercising rats was strongly correlated with object recognition memory. Exercise also decreased anxiety-like behavior, however there was no evidence to support a relationship between anxiety-like behavior and performance on the novel object recognition task. There was a trend for a negative relationship between anxiety-like behavior and hippocampal BDNF. Neither the cognitive improvements nor the relationship between cognitive function and perirhinal BDNF levels persisted after 2weeks of inactivity. These are the first data demonstrating that region-specific changes in BDNF protein levels are correlated with exercise-induced improvements in non-spatial memory, mediated by structures outside the hippocampus and are consistent with the theory that, with regard to object recognition, the anxiolytic and cognitive effects of exercise may be mediated through separable mechanisms.

Voluntary physical exercise alters attentional orienting and social behavior in a rat model of attention-deficit/hyperactivity disorder.

The effects of voluntary physical exercise on attentional function and social behavior were examined in male and female spontaneously hypertensive rats (SHR), a commonly used animal model of attention-deficit/hyperactivity disorder (ADHD). Rats in the exercise groups had free access to a running wheel for 2 weeks and then all rats received nonreinforced presentations of a visual stimulus (light) during the 1st training session, followed by daily sessions in which the light was paired with food. Nonexercising male and female SHR rats exhibited more unconditioned orienting behavior than Wistar-Kyoto rats. SHRs also exhibited impaired conditioning when the light was paired with food. Exercise reduced orienting in female SHRs but not in male SHRs. In the social interaction task, nonexercising male and female SHRs interacted more with an unfamiliar rat than Wistar-Kyoto rats. Exercise reduced the number of social interactions in female SHRs but not male SHRs. There were no differences in general locomotor activity observed between the nonexercising and exercising SHRs. These data indicate that exercise may preferentially benefit female SHRs, and has implications for using exercise as an intervention for ADHD and for understanding sex differences in the effects of exercise on behavior.

Chemoprevention of colorectal neoplasia by estrogen: potential role of vitamin D activity.

Postmenopausal hormone replacement therapy lowers colon cancer incidence. In humans, the mechanism is unknown, but animal models suggest that it may involve activation of the vitamin D receptor (VDR) pathway. The aims of our study were to determine whether estrogen intervention affects global gene expression in rectal mucosal biopsies and whether vitamin D-related genes are affected. Estradiol was given to raise serum estradiol to premenopausal levels in 10 postmenopausal women under close nutritional control. Primary end points were expression of VDR, CYP24A1, CYP27B1, and E-cadherin in rectal mucosa by reverse transcription-PCR and examining response to estradiol by genome-wide arrays. Responses in gene expression in rectal biopsies to estrogen were determined in each subject individually and compared with a human estrogen response gene array database and a custom array in vitro-generated database. Cluster analysis showed that subjects maintained their overall gene expression profile and that interindividual differences were greater than intraindividual differences after intervention. Eight of 10 subjects showed significant enrichment in estrogen-responsive genes. Gene array group analysis showed activation of the VDR pathway and down-regulation of inflammatory and immune signaling pathways. Reverse transcription-PCR analysis showed significant up-regulation of VDR and E-cadherin, a downstream target of vitamin D action. These data suggest that the chemopreventive action of hormone replacement therapy on colon neoplasia results, at least in part, from changes in vitamin D activity. Evaluation of gene arrays is useful in chemopreventive intervention studies in small groups of subjects.

Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response.

Polyisoprenylated benzophenones derived from Garcinia xanthochymus have cytotoxic activity in vitro and antitumor activity in rodent models, but the mechanism is unknown. The purpose of our study was to examine in parallel molecular pathways that are targeted by 3 Garcinia-derived benzophenones-xanthochymol (X), guttiferone E (GE) and guttiferone H (GH), in 3 human colon cancer cell lines, HCT116, HT29 and SW480. The IC50 concentrations were determined and the cells were then treated with X, GE or GH at their respective IC50 or IC50x2 concentrations. Effects on the cell cycle, mitochondrial membrane potential and apoptosis were assessed by flow cytometry and caspase activation. Changes in gene expression were assessed with Illumina 24 K gene arrays. We found that X, GE and GH induced loss of mitochondrial membrane potential and G1 arrest at their IC50 concentrations and induced caspase activation at IC50 x 2 concentrations. An analysis of the changes in gene expression revealed that with all 3 compounds and all 3 cell lines there was a marked increase in expression of several genes, including XBP1, ATF4 and DDIT3/CHOP, which are components of the endoplasmic reticulum stress response. The DDIT4/REDD1 gene, an inhibitor of the mTOR survival pathway, was also up-regulated. Therefore, X, GE and GH appear to inhibit the growth of human colon cancer cells, at least in part, by activating the endoplasmic reticulum stress response and inhibiting the mTOR cell survival pathway. These combined effects may contribute to the anticancer activity of these novel compounds.

Sex differences in learning and inhibition in spontaneously hypertensive rats.

Few studies have addressed potential differences in the nature of cognitive impairment observed in males and females with ADHD. In Experiment 1, we examined sex differences in conditioned inhibitory behaviour in spontaneously hypertensive rats (SHR strain), a purported animal model of ADHD. Rats were presented with two types of trials during each of the 15 conditioning sessions. On some trials an auditory stimulus (a tone) was presented and followed immediately by delivery of food reward. On the remaining trials the tone was preceded by presentation of a visual stimulus and on those trials food was not delivered after the tone was presented. As training progressed, conditioned responding during presentation of the tone increased on reinforced trials and decreased during the non-reinforced trials, indicative of successful discrimination and inhibition. Overall, female SHR rats exhibited less conditioned overall food cup behaviour compared to male rats. Female SHR rats also required more training sessions until they responded significantly more during presentation of the tone on reinforced trials versus non-reinforced trials. In addition, the magnitude of the discrimination was smaller in female SHR rats compared to males. In contrast, no sex differences were observed in WKY rats (commonly-used control strain) in Experiment 2. Importantly, there were no significant sex differences in baseline activity or motivation during either experiment, indicating that performance differences could not account for the observed results. These results suggest that male and female SHR rats differ in their ability to form conditioned associations and inhibit behavioural responses and may provide a useful model for sex differences in cognitive dysfunction specific to ADHD.

Effects of sex hormones on associative learning in spontaneously hypertensive rats.

Pavlovian conditioning of a visual stimulus paired with food was examined in spontaneously hypertensive rats (SHR), which are a commonly used model for Attention-Deficit/Hyperactivity Disorder (ADHD), and in Wistar rats (normoactive control). In gonadally intact rats of both strains, males spent more time in the food cup following onset of the light than did females, indicating a stronger association of the conditioned stimulus (CS) with reward. Gonadectomy carried out in adulthood affected conditioning differently in the two strains. In Wistar rats, gonadectomy had no effect on conditioned responding in females, but reduced conditioned responding in males, effectively eliminating the sex difference in behavior. This result suggests that circulating androgens in male Wistar rats normally aid conditioning in this task. In contrast, gonadectomy enhanced conditioning in both sexes in the SHR rats, indicating that androgens and/or estrogens impair conditioned associations in this strain. These data indicate that gonadal steroids can influence conditioning in rats and that the valence of steroid action on this behavior is strain-dependent. To the extent that SHR serves as a model of ADHD in humans, the influence of steroids on associative learning may play a role in the expression of ADHD-like behaviors.