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Supplementary Tables 1-11 includes GISTIC results, clinical characteristics, details on cell lines and MACROD2 deletions, pathogenicity predictions, metaphase chromosomes anomalies, multivariate analyses and primer sequences.

Supplementary Figures 1-23 including results for fine mapping of MACROD2 deletions, xenograft assay, immunofluoresence, comet assays, western blots, PARP1 activity assays, clonogenic assays, apoptosis assays, metaphase spreads and chromosome missegregation quantification.

Supplementary Methods for generation of CRISPR and stable cell lines, MACROD2 mutation detection, QRT-PCR, phenotyping of MACROD2/APCmin mice, IHC, WB, TCF reporter assay, RNAseq analysis, generation of MACROD2 antibody, clonogenic assay, PARP1 activity assay, apoptosis assays, IF and FACS analysis.

Mouse phenotyping data

BACKGROUND: Bell's palsy is a lower motor neurone facial weakness of unknown aetiology, although reactivation of a virus within the facial nerve has been proposed. METHODS: A prospective study was conducted of Bell's palsy cases presenting to our paediatric ENT unit over a 19-week period, from February to June 2020. Patients were invited for severe acute respiratory syndrome coronavirus-2 antibody testing. A text-message questionnaire was sent to other ENT centres to determine their observational experience. RESULTS: During the study period, 17 children presented with Bell's palsy, compared with only 3 children in the same time period in the previous year (p < 0.0001). Five patients underwent severe acute respiratory syndrome coronavirus-2 antibody testing, the results of which were all negative. Four out of 15 centres questioned perceived an increased incidence in paediatric Bell's palsy. CONCLUSION: Clinicians are encouraged to be vigilant to the increase in paediatric Bell's palsy seen during the coronavirus disease 2019 pandemic, which may represent a post-viral sequela of coronavirus disease 2019.

BackgroundCold dissection is the most commonly used tonsillectomy technique, with low post-operative haemorrhage rates. Coblation is an alternative technique that may cause less pain, but could have higher post-operative haemorrhage rates.ObjectiveThis study evaluated the peri-operative outcomes in paediatric tonsillectomy patients by comparing coblation and cold dissection techniques.MethodsA systematic review was conducted of all comparative studies of paediatric coblation and cold dissection tonsillectomy, up to December 2018. Any studies with adults were excluded. Outcomes such as pain, operative time, and intra-operative, primary and secondary haemorrhages were recorded.ResultsSeven studies contributed to the summative outcome. Coblation tonsillectomy appeared to result in less pain, less intra-operative blood loss (p < 0.01) and a shorter operative time (p < 0.01). There was no significant difference between the two groups for post-operative haemorrhage (p > 0.05).ConclusionThe coblation tonsillectomy technique may offer better peri-operative outcomes when compared to cold dissection, and should therefore be offered in paediatric cases, before cold dissection tonsillectomy.

BackgroundCoronavirus disease 2019 personal protective equipment has been reported to affect communication in healthcare settings. This study sought to identify those challenges experimentally.MethodBamford–Kowal–Bench speech discrimination in noise performance of healthcare workers was tested under simulated background noise conditions from a variety of hospital environments. Candidates were assessed for ability to interpret speech with and without personal protective equipment, with both normal speech and raised voice.ResultsThere was a significant difference in speech discrimination scores between normal and personal protective equipment wearing subjects in operating theatre simulated background noise levels (70 dB).ConclusionWearing personal protective equipment can impact communication in healthcare environments. Efforts should be made to remind staff about this burden and to seek alternative communication paradigms, particularly in operating theatre environments.

Background Coronavirus disease 2019(Covid-19) Personal Protective Equipment (PPE) has been reported to effect communication in healthcare settings. We sought to identify those challenges experimentally. Method Bamford-Kowal-Bench speech discrimination in noise performance of healthcare workers was tested under simulated background noise conditions from a variety of hospital environments. Candidates were assessed for speech intelligibility with and without PPE both at normal speech and raised voice. Results There was a significant difference in speech discrimination scores between normal and PPE wearing subjects in theatre simulated background noise levels (70dB). Conclusion PPE wearing can impact communication and efforts should be made to remind staff about this burden and seek alternative communication paradigms, particularly in theatre environments.

Introduction: It is difficult to accurately identify aetiological factors causing breathlessness (symptoms disproportionate to those expected from a given diagnosis that impacts on the ability to exercise). Effective management relies on an accurate diagnosis. Aims: To review routinely collected diagnostic and clinical data of children referred to the complex breathlessness clinic. Methods: Routinely collected data was analysed from May 2017-Jan 2019 from one of the only paediatric complex breathlessness clinics in Europe. Children (including high level athletes) were referred across North West England. The structured diagnostic process included clinical assessment (respiratory, physiotherapy, ENT), physiological measurement, and laryngoscopy pre and post exercise. Tailored follow-up therapy was directed by a specialist physiotherapist. Results: 32 children attended clinic (age 7-18 [mean 14] years; 25/32 [78%] female). 12/32 (38%) were high level athletes; 4/32 (12.5%) were ex-athletes. Aetiological diagnoses identified were: Dysfunctional breathing 17/32 (53%), Deconditioning 12/32 (39%), Anxiety or other psychosocial factors 12/32 (38%), Laryngeal obstruction 9/32 (29%), Asthma 7/32 (22%), Exercise-induced bronchoconstriction 2/32 (6%) and Reaching maximal exercise capacity 2/32 (6%). Following specialist therapies, 23/32(72%) children were discharged due to resolution of symptoms, 6/32 (19%) are currently receiving treatment and 3/32 (9%) did not attend follow-up therapy. Conclusion: Complex breathlessness is caused by multiple factors, and requires a multispecialty diagnostic approach. Tailored therapies had a positive impact on children with complex breathlessness.

Hoarseness or dysphonia are terms used to describe a change in the quality of the voice. The voice quality can be raspy, breathy, strained, fatigued, rough, tremulous or weak. There may be a change in pitch, restriction of range, voice breaks, decreased projection, or abnormal resonance. It is important to remember that a voice disorder is not a disease in itself but rather a presentation of an underlying pathology. Clinicians' knowledge of paediatric hoarseness is limited as it can be difficult to examine children using fibreoptic laryngoscopy and the child may not comprehend the need for detailed examination. However, paediatric flexible naso-laryngoscopy provides a dynamic view of the laryngeal anatomy and function. Recent advances in diagnostic equipment, pharmacology and therapeutics mean that this problem can be managed more successfully but it still remains a challenge. This article discusses the presentation, aetiology and management of hoarseness in children.

Over the past few years, all three of us have left academia. It was the right decision for each of us, but we still struggled with uncertainty and a feeling of failure, and we could find little community support. We thought that sharing our experiences could help others in similar situations, so we

Over the past two decades, as part of reforms to the National Health Service (NHS) and with it organizational changes to ambulance work in the UK, paramedic education has undergone a process of academisation and a shift from in-house, apprenticeship weeks-long occupational training, to university-based undergraduate programs. While the professional regulation and standardization of Allied Health Professionals’ (AHPs) education in high-income countries has captured scholarly attention, the study of paramedic practice is still in its infancy and there is a need to explore its evolvement in relation to the fluid societal-political circumstances affecting its provision and demand. Based on interviews with front-line paramedics, paramedic educators and Paramedic Science students in the South of England, this article examines how the reforms to paramedic education have impacted the professionalization of paramedics and their discourse of professionalism. Framed within to the ‘new’ sociology of professions, the case of British paramedics demonstrates the complex nature of the relationship between the university and professional practice. It appears that universities, the providers of paramedic education, are caught between two opposing discourses of professionalism: on the one hand, that of providing a platform for students’ socialization and engagement with professionalism ‘from within’ practice which is based on students’ common goals and mutual experiences, and, on the other hand, serving as a conduit for managerial/organizational strategies of professionalism which appear to undermine the role of university socialization.

To assess the long-term outcome of lipomas affecting the cerebellopontine angle (CPA) and internal auditory canal (IAC).This is a retrospective, single-center study of 10 CPA and IAC lipomas that have presented for the last 6 years. There were 8 male and 2 female patients whose age ranged from 22 to 71 years. These lesions were distributed equally between left and right sides.The natural progression, audiovestibular signs and symptoms, imaging characteristics, and management options have been evaluated.Long-term clinical outcome was correlated with serial imaging and audiograms.The most common presenting feature was hearing loss with an average lesion size of 8 mm. Two patients experienced imbalance, with one requiring operative intervention for incapacitating vertigo. The other 9 were managed conservatively. Follow-up imaging was available for 8 cases, and no growth was observed in any of these, with an average follow-up of 3.5 years.Because of the resolution of modern imaging, lipomas of the IAC and CPA are increasingly being recognized and accurately diagnosed. Our data suggest that these lesions are more common than previously thought, representing approximately 1% of all lesions in this location referred to our center. With the absence of growth in 8 cases with follow-up average of 3.5 years as our basis, we recommend that these lesions are managed conservatively by serial imaging. In rare cases, surgery may be required if the lesion is resulting in incapacitating symptoms, such as significant balance disturbance.

Infections of the ear, nose and throat are exceedingly common. Foreign bodies also frequently become impacted in these cavities. These problems affect all age groups and both sexes. Initially, most of these infections can be dealt with medically. A prompt decision for surgical intervention is usually needed if medical therapy is not working. If the airway is under threat, an immediate surgical opinion is necessary. Purulent collections will often require incision and drainage. An understanding of the anatomy of the area is therefore essential. Foreign bodies, however, almost invariably require surgical intervention. The urgency of this is dictated by the foreign body itself and the site of impaction.

Mice deficient in SOCS2 display an excessive growth phenotype characterized by a 30–50% increase in mature body size. Here we show that the SOCS2–/– phenotype is dependent upon the presence of endogenous growth hormone (GH) and that treatment with exogenous GH induced excessive growth in mice lacking both endogenous GH and SOCS2. This was reflected in terms of overall body weight, body and bone lengths, and the weight of internal organs and tissues. A heightened response to GH was also measured by examining GH-responsive genes expressed in the liver after exogenous GH administration. To further understand the link between SOCS2 and the GH-signaling cascade, we investigated the nature of these interactions using structure/function and biochemical interaction studies. Analysis of the 3 structural motifs of the SOCS2 molecule revealed that each plays a crucial role in SOCS2 function, with the conserved SOCS-box motif being essential for all inhibitory function. SOCS2 was found to bind 2 phosphorylated tyrosines on the GH receptor, and mutational analysis of these amino acids showed that both were essential for SOCS2 function. Together, the data provide clear evidence that SOCS2 is a negative regulator of GH signaling.

Cytosolic PLA2 (cPLA2) has been implicated in the release of the arachidonic acid utilized in the inflammatory cascade. Phosphorylation of cPLA2 on Ser-505 by MAP kinase in response to agonist treatment, is thought to be one of the mechanisms required for activation of the enzyme in the cell. In order to obtain enough material for enzymological studies as well as to investigate the role of phosphorylation in the activation of cPLA2, the human enzyme was overexpressed in insect cells using a recombinant baculovirus. We report here on the characterization of the phosphorylation state of cPLA2 overexpressed in Sf9 cells. The level of overexpressed cPLA2 was shown to peak between 48 and 60 h post-infection, by this time the phosphorylated enzyme could easily be detected because of its reduced mobility on polyacrylamide gels. The reduced mobility or gel-shift has been shown to be due to phosphorylation of Ser-505. To determine whether this was also the case for insect cell overexpressed cPLA2, Ser-505 was replaced by Ala, and this mutant (cPLA2S505A) was expressed in Sf9 cells. Analysis of the overexpressed cPLA2S505A showed that it migrated only as the lower unshifted cPLA2 band confirming that the baculovirus overexpressed cPLA2 is extensively phosphorylated on Ser-505. Furthermore, treatment of infected Sf9 cells expressing the wild-type cPLA2 with phorbol 12-tetradecanoate 13-acetate (TPA) shifted all of the overexpressed cPLA2 to the phosphorylated Ser-505 form. When infected Sf9 cells were labelled with [32P], in addition to labelling of Ser-505 other sites were also labelled. Both cPLA2 and cPLA2S505A were purified from infected Sf9 cells and the specific activity for each of the enzymes was measured in a phosphatidylcholine vesicle fluorescence assay using 1-(10-pyrenedecanyl)arachidonyl-sn-glycero-3-phosphocholine as substrate. Under these conditions the specific activity of cPLA2 was, 2 mumol/min per mg, whereas cPLA2S505A was 7-fold less active. These findings suggest that Sf9 cells have a mechanism for phosphorylating cPLA2 similar to that found in mammalian cells which probably proceeds through a MAP kinase. Thus, insect cell overexpressed cPLA2 is a very good source for the Ser-505 phosphorylated enzyme.

OBJECTIVE: To systematically review the literature on harmonic scalpel tonsillectomy with a view of comparing its postoperative hemorrhagic rate with the conventional methods for tonsillectomy. DATA SOURCES: Cochrane Library, Medline, Embase, CINAHL, INAHTA, CRD (Centre for Review and Dissemination, York, UK), and related databases. The date of the last search was September 19, 2006; papers were considered irrespective of language of publication. REVIEW METHODS: Inclusion and exclusion criteria were applied independently by two reviewers with a third reviewer available for adjudication. The papers were quality assessed using Chalmers' criteria. Eleven randomized controlled trials (RCT) were included in the final review with five RCTs comparing harmonic scalpel tonsillectomy with “cold steel” tonsillectomy and six RCTs comparing harmonic scalpel with “hot” tonsillectomy techniques. RESULTS: All studies were underpowered to detect a significant difference in the postoperative hemorrhagic complication between harmonic scalpel and the comparator tonsillectomy techniques. The heterogeneity of studies made quantitative combination of results impossible. CONCLUSION: The evidence reviewed is of low quality and does not support any significant difference in postoperative hemorrhage rates when harmonic scalpel is compared with other tonsillectomy techniques. As studies have numerous methodological flaws and incorporate biases and confounding factors, these results need to be interpreted with caution. Larger and better-conducted studies would be needed in order to compare the safety of harmonic against conventional tonsillectomy methods. The need for a large sample size might make an RCT impractical; therefore a large, well-controlled cohort study could be more suitable.