Mapping Human Immunity and the Education of Waldeyer's Ring.

The development and deployment of single-cell genomic technologies have driven a resolution revolution in our understanding of the immune system, providing unprecedented insight into the diversity of immune cells present throughout the body and their function in health and disease. Waldeyer's ring is the collective name for the lymphoid tissue aggregations of the upper aerodigestive tract, comprising the palatine, pharyngeal (adenoids), lingual, and tubal tonsils. These tonsils are the first immune sentinels encountered by ingested and inhaled antigens and are responsible for mounting the first wave of adaptive immune response. An effective mucosal immune response is critical to neutralizing infection in the upper airway and preventing systemic spread, and dysfunctional immune responses can result in ear, nose, and throat pathologies. This review uses Waldeyer's ring to demonstrate how single-cell technologies are being applied to advance our understanding of the immune system and highlight directions for future research.

An atlas of cells in the human tonsil.

Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil.

A systematic review of antimicrobial therapy in children with tracheostomies.

Tracheostomies are indicated in children to facilitate long-term ventilatory support, aid in the management of secretions, or manage upper airway obstruction. Children with tracheostomies often experience ongoing airway complications, of which respiratory tract infections are common. They subsequently receive frequent courses of broad-spectrum antimicrobials for the prevention or treatment of respiratory tract infections. However, there is little consensus in practice with regard to the indication for treatment/prophylactic antimicrobial use, choice of antimicrobial, route of administration, or duration of treatment between different centers. Routine antibiotic use is associated with adverse effects and an increased risk of antimicrobial resistance. Tracheal cultures are commonly obtained from pediatric tracheostomy patients, with the aim of helping guide antimicrobial therapy choice. However, a positive culture alone is not diagnostic of infection and the role of routine surveillance cultures remains contentious. Inhaled antimicrobial use is also widespread in the management of tracheostomy-associated infections; this is largely based on the theoretical benefits of higher airway antibiotic concentrations. The role of prophylactic inhaled antimicrobial use for tracheostomy-associated infections remains largely unproven. This systematic review summarizes the current evidence base for antimicrobial selection, duration, and administration route in pediatric tracheostomy-associated infections. It also highlights significant variation in practice between centers and the urgent need for further prospective evidence to guide the management of these vulnerable patients.

Developing an Evidence-Based Surgical Curriculum: Learning from a Randomized Controlled Trial of Surgical Rehearsal in Virtual Reality.

BACKGROUND: Surgical rehearsal - patient-specific preoperative surgical practice - can be provided by virtual reality simulation. This study investigated the effect of surgical rehearsal on cortical mastoidectomy performance and procedure duration. METHODS: University students (n=40) were randomized evenly into a rehearsal and control group. After watching a video tutorial on cortical mastoidectomy, participants completed the procedure on a virtual reality simulator as a pre-test. Participants completed a further 8 cortical mastoidectomies on the virtual reality simulator as training before drilling two 3-dimensional (3D) printed temporal bones. The rehearsal group received 3D printed bones they had previously operated on in virtual reality, while the control group received 2 new bones. Cortical mastoidectomy was assessed by 3 blinded graders using the Melbourne Mastoidectomy Scale. RESULTS: There was high interrater reliability between the 3 graders (intraclass correlation coefficient, r=0.8533, P < .0001). There was no difference in the mean surgical performance on the two 3D printed bones between the control and rehearsal groups (P=.2791). There was no significant difference in the mean procedure duration between the control and rehearsal groups for both 3D printed bones (P=.8709). However, there was a significant decrease in procedure duration between the first and second 3D printed bones (P < .0001). CONCLUSION: In this study, patient-specific virtual reality rehearsal provided no additional advantage to cortical mastoidectomy performance by novice operators compared to generic practice on a virtual reality simulator. Further, virtual reality training did not improve cortical mastoidectomy performance on 3D printed bones, highlighting the impact of anatomical diversity and changing operating modalities on the acquisition of new surgical skills.

The utility of a symptom model to predict the risk of oesophageal cancer.

OBJECTIVE: To assess whether extra-oesophageal symptoms are predictive of oesophageal malignancy. METHODS: A prospective, single-centre cross-sectional questionnaire study at a tertiary referral unit for oesophageal cancer using the Comprehensive Reflux Symptoms Scale (CReSS) questionnaire tool. Respondents with oesophageal malignancy were compared with historical cohorts undergoing airway examination or upper gastrointestinal endoscopy and found to have benign diagnoses. We developed a model for predicting oesophageal cancer using linear discriminant analysis and logistic regression, assessed by Monte Carlo cross validation. RESULTS: Respondents with oesophageal malignancy (n = 146; mean age 70.5; male: female, 71:29) were compared with those undergoing airway examination (n = 177) and upper gastrointestinal endoscopy (n = 351), found to have benign diagnoses. No single questionnaire item, or group of co-varying items (factors), reliably discriminated oesophageal cancer from other diagnoses. Individual items which suggested higher risk of oesophageal malignancy included dysphagia (area under the curve (AUC) 0.68), low appetite (AUC 0.66), and early satiety (AUC 0.58). Conversely, throat pain (AUC 0.38), bloating (AUC 0.38) and heartburn (AUC 0.37) were inversely related to cancer risk. A forward stepwise regression analysis including a subset of 12 CReSS questionnaire items together with age and sex derived a model predictive of oesophageal malignancy in this cohort (AUC 0.89). CONCLUSION: We demonstrate a model comprised of 12 questionnaire items and 2 demographic parameters as a potential predictive tool for oesophageal malignancy diagnosis in this study population. Translating this model for predicting oesophageal malignancy in the general population is a valuable topic for future research.

Baseline Psychological Traits Contribute to Lake Louise Acute Mountain Sickness Score at High Altitude.

Talks, Benjamin James, Catherine Campbell, Stephanie J. Larcombe, Lucy Marlow, Sarah L. Finnegan, Christopher T. Lewis, Samuel J.E. Lucas, Olivia K. Harrison, and Kyle T.S. Pattinson. Baseline psychological traits contribute to Lake Louise Acute Mountain Sickness score at high altitude. High Alt Med Biol. 23:69-77, 2022. Background: Interoception refers to an individual's ability to sense their internal bodily sensations. Acute mountain sickness (AMS) is a common feature of ascent to high altitude that is only partially explained by measures of peripheral physiology. We hypothesized that interoceptive ability may explain the disconnect between measures of physiology and symptom experience in AMS. Methods: Two groups of 18 participants were recruited to complete a respiratory interoceptive task three times at 2-week intervals. The control group remained in Birmingham (140 m altitude) for all three tests. The altitude group completed test 1 in Birmingham, test 2 the day after arrival at 2,624 m, and test 3 at 2,728 m after an 11-day trek at high altitude (up to 4,800 m). Results: By measuring changes to metacognitive performance, we showed that acute ascent to altitude neither presented an interoceptive challenge, nor acted as interoceptive training. However, AMS symptom burden throughout the trek was found to relate to sea level measures of anxiety, agoraphobia, and neuroticism. Conclusions: This suggests that the Lake Louise AMS score is not solely a reflection of physiological changes on ascent to high altitude, despite often being used as such by researchers and commercial trekking companies alike.

Dysregulation of immune response in otitis media.

OBJECTIVE: Otitis media (OM) is a common reason for children to be prescribed antibiotics and undergo surgery but a thorough understanding of disease mechanisms is lacking. We evaluate the evidence of a dysregulated immune response in the pathogenesis of OM. METHODS: A comprehensive systematic review of the literature using search terms [otitis media OR glue ear OR AOM OR OME] OR [middle ear AND (infection OR inflammation)] which were run through Medline and Embase via Ovid, including both human and animal studies. In total, 82 955 studies underwent automated filtering followed by manual screening. One hundred studies were included in the review. RESULTS: Most studies were based on in vitro or animal work. Abnormalities in pathogen detection pathways, such as Toll-like receptors, have confirmed roles in OM. The aetiology of OM, its chronic subgroups (chronic OM, persistent OM with effusion) and recurrent acute OM is complex; however, inflammatory signalling mechanisms are frequently implicated. Host epithelium likely plays a crucial role, but the characterisation of human middle ear tissue lags behind that of other anatomical subsites. CONCLUSIONS: Translational research for OM presently falls far behind its clinical importance. This has likely hindered the development of new diagnostic and treatment modalities. Further work is urgently required; particularly to disentangle the respective immune pathologies in the clinically observed phenotypes and thereby work towards more personalised treatments.

Automated assessment of cortical mastoidectomy performance in virtual reality.

INTRODUCTION: Cortical mastoidectomy is a core skill that Otolaryngology trainees must gain competency in. Automated competency assessments have the potential to reduce assessment subjectivity and bias, as well as reducing the workload for surgical trainers. OBJECTIVES: This study aimed to develop and validate an automated competency assessment system for cortical mastoidectomy. PARTICIPANTS: Data from 60 participants (Group 1) were used to develop and validate an automated competency assessment system for cortical mastoidectomy. Data from 14 other participants (Group 2) were used to test the generalisability of the automated assessment. DESIGN: Participants drilled cortical mastoidectomies on a virtual reality temporal bone simulator. Procedures were graded by a blinded expert using the previously validated Melbourne Mastoidectomy Scale: a different expert assessed procedures by Groups 1 and 2. Using data from Group 1, simulator metrics were developed to map directly to the individual items of this scale. Metric value thresholds were calculated by comparing automated simulator metric values to expert scores. Binary scores per item were allocated using these thresholds. Validation was performed using random sub-sampling. The generalisability of the method was investigated by performing the automated assessment on mastoidectomies performed by Group 2, and correlating these with scores of a second blinded expert. RESULTS: The automated binary score compared with the expert score per item had an accuracy, sensitivity and specificity of 0.9450, 0.9547 and 0.9343, respectively, for Group 1; and 0.8614, 0.8579 and 0.8654, respectively, for Group 2. There was a strong correlation between the total scores per participant assigned by the expert and calculated by the automatic assessment method for both Group 1 (r = .9144, P < .0001) and Group 2 (r = .7224, P < .0001). CONCLUSION: This study outlines a virtual reality-based method of automated assessment of competency in cortical mastoidectomy, which proved comparable to the assessment provided by human experts.

The Melbourne Mastoidectomy Scale: Validation of an end-product dissection scale for cortical mastoidectomy.

INTRODUCTION: Cortical mastoidectomy is a common otolaryngology procedure and represents a compulsory part of otolaryngology training. As such, a specific validated assessment score is needed for the progression of competency-based training in this procedure. Although multiple temporal bone dissection scales have been developed, they have all been validated for advanced temporal bone dissection including posterior tympanotomy, rather than the task of cortical mastoidectomy. METHODS: The Melbourne Mastoidectomy Scale, a 20-item end-product dissection scale to assess cortical mastoidectomy, was developed. The scale was validated using dissections by 30 participants (10 novice, 10 intermediate and 10 expert) on a virtual reality temporal bone simulator. All dissections were assessed independently by three blinded graders. Additionally, all procedures were graded with an abbreviated Welling Scale by one grader. RESULTS: There was high inter-rater reliability between the three graders (r = .9210, P < .0001). There was a significant difference in scores between the three groups (P < .0001). Additionally, there was a large effect size between all three groups: the differences between the novice group and both the intermediate group (P = .0119, η2  = 0.2482) and expert group (P < .001, η2  = 0.6356) were significant. The difference between the intermediate group and expert group again had a large effect size (η2  = 0.3217), but was not significant. The Melbourne Mastoidectomy Scale correlated well with an abbreviated Welling Scale (r = .8485, P < .0001). CONCLUSION: The Melbourne Mastoidectomy Scale offers a validated score for use in the assessment of cortical mastoidectomy.

No Evidence of Systemic Inflammation in Symptomatic Patients With Femoroacetabular Impingement.

Femoroacetabular impingement (FAI) is a common cause of hip pain and represents a major cause of early osteoarthritis. The role of systemic inflammation in pre-arthritic hip conditions remains largely unknown and uninvestigated. Serum-free light chains (sFLCs) are inflammatory markers produced by B cells. This study aimed to determine whether there was evidence of systemic inflammation in patients with FAI, defined by sFLCs, and whether this correlated with markers of disease severity. Participants for this study were recruited from a single center (Nuffield Orthopedic Center, Oxford) and were taking part in the Femoroacetabular Impingement Trial. The cohort comprised 115 individuals (38 male, 77 female, mean age 37 years): 57 individuals received surgical intervention and 58 received physiotherapy. All individuals provided patient-reported outcome measures and serum samples at baseline and follow-up 8 months post-randomization. sFLC concentrations were measured in serum samples by immunoturbidimetry. At baseline, for all individuals, mean polyclonal sFLC concentrations were 30.36 mg/l (standard deviation [SD] 9.23). At follow-up, the mean polyclonal sFLC concentrations were 31.68 mg/l (SD 9.61) in the surgical intervention cohort, and 29.48 mg/l (SD 7.85) in the physiotherapy intervention cohort. There was no significant correlation between sFLC concentrations and any of the patient reported outcome measures, or radiographic measures: average or maximum alpha angle, or center edge angle. In conclusion, in patients with symptomatic FAI there was no systemic inflammation, as defined by sFLC concentrations, and no correlation between sFLC concentrations and measures of disease severity. The lack of inflammation suggests FAI is a mechanical phenomenon. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2189-2196, 2019.