Poor correlation between airway fluoroscopy and rigid bronchoscopic evaluation in paediatric tracheomalacia.

INTRODUCTION: Tracheomalacia is a common congenital condition causing stridor in young children. However, the evaluation of these children remains poorly standardised across institutions. METHODS: We conducted a retrospective review of all children undergoing an elective laryngotracheobronchoscopy at a single tertiary paediatric institution between March 2010 and December 2018. Emergency bronchoscopies and children with tracheostomies were excluded. 1163 children undergoing an elective bronchoscopy were included in this study, and 545 children also had an airway fluoroscopy. RESULTS: The median age at bronchoscopy was 17 months, and the majority of children were male. Tracheomalacia was diagnosed in 21.6% of children at bronchoscopy, of these 48.5% had tracheomalacia diagnosed on a previous airway fluoroscopy. Overall, airway fluoroscopy had a low sensitivity (62.3%) and a low specificity (67.5%) for diagnosis of tracheomalacia when compared with bronchoscopy. Increasing severity of tracheomalacia on airway screen significantly predicted a diagnosis of tracheomalacia on bronchoscopy. CONCLUSIONS: Airway fluoroscopy has a low sensitivity and specificity in diagnosis of tracheomalacia and should be used judiciously rather than as a screening tool for children with stridor. However, this imaging technique may be beneficial in investigating children with severe symptoms who have had other conditions such as laryngomalacia excluded.

Cross validated serum small extracellular vesicle microRNAs for the detection of oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is often diagnosed at an advanced stage because the disease often causes minimal symptoms other than metastasis to neck lymph nodes. Better tools are required to assist with the early detection of OPSCC. MicroRNAs (miRNAs, miRs) are potential biomarkers for early head and neck squamous cell cancer diagnosis, prognosis, recurrence, and presence of metastatic disease. However, there is no widespread agreement on a panel of miRNAs with clinically meaningful utility for head and neck squamous cell cancers. This could be due to variations in the collection, storage, pre-processing, and isolation of RNA, but several reports have indicated that the selection and reproducibility of biomarkers has been widely affected by the methods used for data analysis. The primary analysis issues appear to be model overfitting and the incorrect application of statistical techniques. The purpose of this study was to develop a robust statistical approach to identify a miRNA signature that can distinguish controls and patients with inflammatory disease from patients with human papilloma virus positive (HPV +) OPSCC. METHODS: Small extracellular vesicles were harvested from the serum of 20 control patients, 20 patients with gastroesophageal reflux disease (GORD), and 40 patients with locally advanced HPV + OPSCC. MicroRNAs were purified, and expression profiled on OpenArray™. A novel cross validation method, using lasso regression, was developed to stabilise selection of miRNAs for inclusion in a prediction model. The method, named StaVarSel (for Stable Variable Selection), was used to derive a diagnostic biomarker signature. RESULTS: A standard cross validation approach was unable to produce a biomarker signature with good cross validated predictive capacity. In contrast, StaVarSel produced a regression model containing 11 miRNA ratios with potential clinical utility. Sample permutations indicated that the estimated cross validated prediction accuracy of the 11-miR-ratio model was not due to chance alone. CONCLUSIONS: We developed a novel method, StaVarSel, that was able to identify a panel of miRNAs, present in small extracellular vesicles derived from blood serum, that robustly cross validated as a biomarker for the detection of HPV + OPSCC. This approach could be used to derive diagnostic biomarkers of other head and neck cancers.

Prdm12 Directs Nociceptive Sensory Neuron Development by Regulating the Expression of the NGF Receptor TrkA.

In humans, many cases of congenital insensitivity to pain (CIP) are caused by mutations of components of the NGF/TrkA signaling pathway, which is required for survival and specification of nociceptors and plays a major role in pain processing. Mutations in PRDM12 have been identified in CIP patients that indicate a putative role for this transcriptional regulator in pain sensing. Here, we show that Prdm12 expression is restricted to developing and adult nociceptors and that its genetic ablation compromises their viability and maturation. Mechanistically, we find that Prdm12 is required for the initiation and maintenance of the expression of TrkA by acting as a modulator of Neurogenin1/2 transcription factor activity, in frogs, mice, and humans. Altogether, our results identify Prdm12 as an evolutionarily conserved key regulator of nociceptor specification and as an actionable target for new pain therapeutics.

A third HSAN5 mutation disrupts the nerve growth factor furin cleavage site.

Bi-allelic dysfunctional mutations in nerve growth factor (NGF) cause the rare human phenotype hereditary sensory and autonomic neuropathy type 5 (HSAN5). We describe a novel NGF mutation in an individual with typical HSAN5 findings. The mutation c.361C>T, p.R121W is at the last residue of the furin cleavage motif Arg-Ser-Lys-Arg in proNGF. We show that the p.R121W mutation completely abolishes the formation of mature NGF-ß. Surprisingly, mutant p.R121W cells produced very little proNGF. Instead, the two progressive cleavage products of proNGF were produced, proA-NGF and proB-NGF, with proB-NGF being the predominant NGF-derived peptide and the only peptide secreted by mutant p.R121W cells. We found that the ability of the p.R121W mutation to cause tropomyosin receptor kinase A autophosphorylation and mitogen-activated protein kinase phosphorylation was significantly reduced compared to controls (p < 0.05 and p < 0.01). By studying the PC12 cell line morphology and neurite length over a week, we found the p.R121W mutation had residual, but much reduced, neurotrophic activity when compared to wild-type NGF. Finally, we assessed whether the p.R121W mutation affected apoptosis and found a reduced protective effect compared to wild-type NGF. Our results suggest that the p.R121W NGF mutation causes HSAN5 through negating the ability of furin to cleave proNGF to produce NGF-ß.

L718Q mutant EGFR escapes covalent inhibition by stabilizing a non-reactive conformation of the lung cancer drug osimertinib.

Osimertinib is a third-generation inhibitor approved for the treatment of non-small cell lung cancer. It overcomes resistance to first-generation inhibitors by incorporating an acrylamide group which alkylates Cys797 of EGFR T790M. The mutation of a residue in the P-loop (L718Q) was shown to cause resistance to osimertinib, but the molecular mechanism of this process is unknown. Here, we investigated the inhibitory process for EGFR T790M (susceptible to osimertinib) and EGFR T790M/L718Q (resistant to osimertinib), by modelling the chemical step (i.e., alkylation of Cys797) using QM/MM simulations and the recognition step by MD simulations coupled with free-energy calculations. The calculations indicate that L718Q has a negligible impact on both the activation energy for Cys797 alkylation and the free-energy of binding for the formation of the non-covalent complex. The results show that Gln718 affects the conformational space of the EGFR-osimertinib complex, stabilizing a conformation of acrylamide which prevents reaction with Cys797.

Isoflurane disrupts excitatory neurotransmitter dynamics via inhibition of mitochondrial complex I.

BACKGROUND: The mechanisms of action of volatile anaesthetics are unclear. Volatile anaesthetics selectively inhibit complex I in the mitochondrial respiratory chain. Mice in which the mitochondrial complex I subunit NDUFS4 is knocked out [Ndufs4(KO)] either globally or in glutamatergic neurons are hypersensitive to volatile anaesthetics. The volatile anaesthetic isoflurane selectively decreases the frequency of spontaneous excitatory events in hippocampal slices from Ndufs4(KO) mice. METHODS: Complex I inhibition by isoflurane was assessed with a Clark electrode. Synaptic function was measured by stimulating Schaffer collateral fibres and recording field potentials in the hippocampus CA1 region. RESULTS: Isoflurane specifically inhibits complex I dependent respiration at lower concentrations in mitochondria from Ndufs4(KO) than from wild-type mice. In hippocampal slices, after high frequency stimulation to increase energetic demand, short-term synaptic potentiation is less in KO compared with wild-type mice. After high frequency stimulation, both Ndufs4(KO) and wild-type hippocampal slices exhibit striking synaptic depression in isoflurane at twice the 50% effective concentrations (EC50). The pattern of synaptic depression by isoflurane indicates a failure in synaptic vesicle recycling. Application of a selective A1 adenosine receptor antagonist partially eliminates isoflurane-induced short-term depression in both wild-type and Ndufs4(KO) slices, implicating an additional mitochondria-dependent effect on exocytosis. When mitochondria are the sole energy source, isoflurane completely eliminates synaptic output in both mutant and wild-type mice at twice the (EC50) for anaesthesia. CONCLUSIONS: Volatile anaesthetics directly inhibit mitochondrial complex I as a primary target, limiting synaptic ATP production, and excitatory vesicle endocytosis and exocytosis.

Clathrin heavy chain 22 contributes to the control of neuropeptide degradation and secretion during neuronal development.

The repertoire of cell types in the human nervous system arises through a highly orchestrated process, the complexity of which is still being discovered. Here, we present evidence that CHC22 has a non-redundant role in an early stage of neural precursor differentiation, providing a potential explanation of why CHC22 deficient patients are unable to feel touch or pain. We show the CHC22 effect on neural differentiation is independent of the more common clathrin heavy chain CHC17, and that CHC22-dependent differentiation is mediated through an autocrine/paracrine mechanism. Using quantitative proteomics, we define the composition of clathrin-coated vesicles in SH-SY5Y cells, and determine proteome changes induced by CHC22 depletion. In the absence of CHC22 a subset of dense core granule (DCG) neuropeptides accumulated, were processed into biologically active 'mature' forms, and secreted in sufficient quantity to trigger neural differentiation. When CHC22 is present, however, these DCG neuropeptides are directed to the lysosome and degraded, thus preventing differentiation. This suggests that the brief reduction seen in CHC22 expression in sensory neural precursors may license a step in neuron precursor neurodevelopment; and that this step is mediated through control of a novel neuropeptide processing pathway.

Healthcare professionals' knowledge and practice of physical activity promotion in cancer care: Challenges and solutions.

Limited research exists regarding healthcare professionals' knowledge and practice of physical activity promotion for cancer survivors in Ireland. There is also a lack of research identifying the barriers experienced by oncology professionals when promoting physical activity, or referring patients to community-based exercise programmes. This study aims to identify healthcare professionals' knowledge, barriers and practices in relation to physical activity promotion for cancer survivors, and to generate guidance regarding the optimisation of the referral process to community-based exercise programmes. Oncology healthcare professionals (n = 114) were invited to participate in two rounds of an online Delphi study. The response rates in rounds one and two were 38% (43/114) and 70% (30/43). Most respondents acknowledged the value of physical activity for cancer survivors (≥86%) and agreed that discussing physical activity with cancer patients was part of their role (88%). However, the majority of recommendations provided to patients did not align with the current physical activity guidelines. Strategies related to four themes that could optimise the referral process to community-based exercise programmes achieved consensus, including providing education to healthcare professionals and patients regarding the benefits of physical activity and the logistics and quality of programmes, and optimising the logistics of the referral process.

Pathophysiology of swallowing following oropharyngeal surgery for obstructive sleep apnea syndrome.

BACKGROUND: Uvulopalatopharyngoplasty (UPPP) and coblation channeling of the tongue (CCT) are oropharyngeal surgeries used to treat obstructive sleep apnea syndrome. The extent to which UPPP and CCT affect pharyngeal swallow has not been determined. We therefore conducted a novel case series study employing high-resolution impedance manometry (HRIM) to quantify the swallowing-related biomechanics following UPPP and/or CCT surgery. METHODS: Twelve patients who underwent UPPP+CCT or CCT only were assessed an average 2.5 years postsurgery. Swallow function data were compared with ten healthy controls. All patients completed the Sydney swallow questionnaire (SSQ). Pharyngeal pressure-flow analysis of HRIM recordings captured key distension, contractility and pressure-flow timing swallow parameters testing 5, 10, and 20 mL volumes of thin and thick fluid consistencies. KEY RESULTS: Postoperative patients had more dysphagia symptoms with five returning abnormal SSQ scores. Swallowing was biomechanically altered compared to controls, consistent with diminished swallowing reserve, largely driven by elevated hypopharyngeal intrabolus pressure due to a reduced capacity to open the upper esophageal sphincter to accommodate larger volumes. CONCLUSIONS & INFERENCES: Patients who have undergone UPPP and/or CCT surgery appear to have a deficiency in normal modulation of the swallowing mechanism and a reduced swallowing functional reserve. We speculate that these changes may become relevant in later life with the onset of age-related stressors to the swallowing mechanism. This case series strikes a note of caution that further studies are needed to determine the role of preoperative swallow assessment in patients undergoing UPPP and/or CCT surgery.

Does gene expression in laryngeal subsites differ between patients with laryngopharyngeal reflux and controls?

OBJECTIVE: To identify laryngeal mRNA gene changes in patients with laryngopharyngeal reflux (LPR). METHOD: Laryngeal biopsies from non-smoking LPR patients (n=10; Reflux Symptom Index (RSI) >12 and a Reflux Finding Score (RFS) >6) and controls (n=9; RSI <12 and RFS <6) were collected from four subsites (true vocal cord, false vocal cord, medial arytenoid and posterior commissure) of the larynx. qRT-PCR analyses were conducted on 20 reflux- and inflammation-related genes, including interleukins 6 and 8, cytokeratins 8 and 14, mucin genes MUC1, MUC2, MUC3B, MUC4, MUC5B, MUC6 and MUC7 and carbonic anhydrase III. Statistical analysis (Mann-Whitney U test) compared gene expression levels between LPR and control groups at each subsite. RESULTS: Site-specific differences in squamous metaplasia and gene expression were noted in LPR patients, with the majority present in the medial arytenoid region. Significant.differences were noted in genes related to mucosal defence and inflammation, including CRNN, CD1d, TGFß-1, MUC2, MUC5B and CDH1. CONCLUSION: Whilst the posterior commissure is commonly identified as the area demonstrating the most significant macroscopic change in LPR, the histological changes and genes assessed here showed more pronounced LPR associated differences in the medial arytenoid. We identified differences in expression of mucin genes, cytokeratin-14 and molecular markers of inflammation. Whilst some of these changes may be metaplasia-related, further evaluation of the mRNA expression of these genes may provide a useful biomarker panel for diagnosis and therapeutic monitoring of LPR.

Cost analysis of injection laryngoplasty performed under local anaesthesia versus general anaesthesia: an Australian perspective.

OBJECTIVE: To conduct a cost analysis of injection laryngoplasty performed in the operating theatre under local anaesthesia and general anaesthesia. METHODS: The retrospective study included patients who had undergone injection laryngoplasty as day cases between July 2013 and March 2016. Cost data were obtained, along with patient demographics, anaesthetic details, type of injectant, American Society of Anesthesiologists score, length of stay, total operating theatre time and surgeon procedure time. RESULTS: A total of 20 cases (general anaesthesia = 6, local anaesthesia = 14) were included in the cost analysis. The mean total cost under general anaesthesia (AU$2865.96 ± 756.29) was significantly higher than that under local anaesthesia (AU$1731.61 ± 290.29) (p < 0.001). The mean operating theatre time, surgeon procedure time and length of stay were all significantly lower under local anaesthesia compared to general anaesthesia. Time variables such as operating theatre time and length of stay were the most significant predictors of the total costs. CONCLUSION: Procedures performed under local anaesthesia in the operating theatre are associated with shorter operating theatre time and length of stay in the hospital, and provide significant cost savings. Further savings could be achieved if local anaesthesia procedures were performed in the office setting.

Hyaluronic acid for post sinus surgery care: systematic review and meta-analysis.

BACKGROUND: Wound healing after endoscopic sinus surgery may result in adhesion formation. Hyaluronic acid may prevent synechiae development. A systematic review was performed to evaluate the current evidence on the clinical efficacy of hyaluronic acid applied to the nasal cavity after sinus surgery. METHODS: Studies using hyaluronic acid as an adjunct treatment following endoscopic sinus surgery for chronic rhinosinusitis were identified. The primary outcome was adhesion formation rates. A meta-analysis was performed on adhesion event frequency. Secondary outcome measures included other endoscopic findings and patient-reported outcomes. RESULTS: Thirteen studies (501 patients) met the selection criteria. A meta-analysis of adhesion formation frequency on endoscopy demonstrated a lower risk ratio in the hyaluronic acid intervention group (42 out of 283 cases) compared to the control group (81 out of 282) of 0.52 (95 per cent confidence interval = 0.37-0.72). Hyaluronic acid use was not associated with any significant adverse events. CONCLUSION: Hyaluronic acid appears to be clinically safe and well tolerated, and may be useful in the early stages after sinus surgery to limit adhesion rate. Further research, including larger randomised controlled trials, is required to evaluate patient- and clinician-reported outcomes of hyaluronic acid post sinus surgery.

A CEP215-HSET complex links centrosomes with spindle poles and drives centrosome clustering in cancer.

Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer. A cell maintains normal centrosome numbers by coupling centrosome duplication with segregation, which is achieved through sustained association of each centrosome with a mitotic spindle pole. Although the microcephaly- and primordial dwarfism-linked centrosomal protein CEP215 has been implicated in this process, the molecular mechanism responsible remains unclear. Here, using proteomic profiling, we identify the minus end-directed microtubule motor protein HSET as a direct binding partner of CEP215. Targeted deletion of the HSET-binding domain of CEP215 in vertebrate cells causes centrosome detachment and results in HSET depletion at centrosomes, a phenotype also observed in CEP215-deficient patient-derived cells. Moreover, in cancer cells with centrosome amplification, the CEP215-HSET complex promotes the clustering of extra centrosomes into pseudo-bipolar spindles, thereby ensuring viable cell division. Therefore, stabilization of the centrosome-spindle pole interface by the CEP215-HSET complex could promote survival of cancer cells containing supernumerary centrosomes.

Long-term quality-of-life outcomes following treatment for adult obstructive sleep apnoea: comparison of upper airway surgery, continuous positive airway pressure and mandibular advancement splints.

OBJECTIVE: Long-term quality-of-life (QOL) outcomes, complications and clinical effectiveness in patients undergoing treatment with upper airway surgery (UAS), continuous positive airway pressure (CPAP) and mandibular advancement splints (MAS) for adult obstructive sleep apnoea (OSA). DESIGN: Retrospective cohort study. SETTING: Multidisciplinary OSA clinic in University teaching hospital. PARTICIPANTS: Consecutive, simultaneously treated patients with OSA undergoing UAS (n = 83), CPAP (n = 83) and MAS (n = 79). MAIN OUTCOME MEASURES: Glasgow Benefit Inventory (GBI), Snoring Severity Scale (SSS), Epworth Sleepiness Score (ESS) and side-effects in all three groups were recorded at a mean of 34.5 months following start of treatment and compared via anova with Bonferroni's adjustment for pairwise comparisons. RESULTS: Upper airway surgery demonstrated a statistically significant QOL benefit over MAS. All three groups showed a significant improvement in SSS with CPAP significantly better than MAS, but equivalent to UAS. Uncomplicated UAS provided a greater QOL outcome than compliant MAS, non-compliant CPAP (P < 0.05) and comparable to compliant CPAP. Patients undergoing UAS with recorded complications still reported equivalent QOL outcomes to compliant CPAP and MAS, suggesting these surgical complications are relatively minor compared to the QOL benefit of OSA treatment. CONCLUSION: Upper airway surgery showed a significant improvement in QOL outcomes compared to non-compliant CPAP or MAS and equivalent benefit to compliant CPAP. This study strongly supports the role for contemporary UAS in OSA when CPAP is not or no longer an option.

Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge.

Exposure to influenza virus triggers a complex cascade of events in the human host. In order to understand more clearly the evolution of this intricate response over time, human volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2), and then had serial peripheral blood samples drawn and tested for the presence of 25 major human cytokines. Nine of 17 (53%) inoculated subjects developed symptomatic influenza infection. Individuals who will go on to become symptomatic demonstrate increased circulating levels of interleukin (IL)-6, IL-8, IL-15, monocyte chemotactic protein (MCP)-1 and interferon (IFN) gamma-induced protein (IP)-10 as early as 12-29 h post-inoculation (during the presymptomatic phase), whereas challenged patients who remain asymptomatic do not. Overall, the immunological pathways of leucocyte recruitment, Toll-like receptor (TLR)-signalling, innate anti-viral immunity and fever production are all over-represented in symptomatic individuals very early in disease, but are also dynamic and evolve continuously over time. Comparison with simultaneous peripheral blood genomics demonstrates that some inflammatory mediators (MCP-1, IP-10, IL-15) are being expressed actively in circulating cells, while others (IL-6, IL-8, IFN-α and IFN-γ) are probable effectors produced locally at the site of infection. Interestingly, asymptomatic exposed subjects are not quiescent either immunologically or genomically, but instead exhibit early and persistent down-regulation of important inflammatory mediators in the periphery. The host inflammatory response to influenza infection is variable but robust, and evolves over time. These results offer critical insight into pathways driving influenza-related symptomatology and offer the potential to contribute to early detection and differentiation of infected hosts.

Development and Validation of Two Screening Assays for the Hepatitis C Virus NS3 Q80K Polymorphism Associated with Reduced Response to Combination Treatment Regimens Containing Simeprevir.

Persons with hepatitis C virus (HCV) genotype 1a (GT1a) infections harboring a baseline Q80K polymorphism in nonstructural protein 3 (NS3) have a reduced virologic response to simeprevir in combination with pegylated interferon-alfa and ribavirin. We aimed to develop, validate, and freely disseminate an NS3 clinical sequencing assay to detect the Q80K polymorphism and potentially other HCV NS3 drug resistance mutations. HCV RNA was extracted from frozen plasma using a NucliSENS easyMAG automated nucleic acid extractor, amplified by nested reverse transcription-PCR, and sequenced using Sanger and/or next-generation (MiSeq) methods. Sanger chromatograms were analyzed using in-house software (RECall), and nucleotide mixtures were called automatically. MiSeq reads were iteratively mapped to the H77 reference genome, and consensus NS3 sequences were generated with nucleotides present at >20% called as mixtures. The accuracy, precision, and sensitivity for detecting the Q80K polymorphism were assessed in 70 samples previously sequenced by an external laboratory. A comparison of the sequences generated by the Sanger and MiSeq methods with those determined by an external lab revealed >98.5% nucleotide sequence concordance and zero discordant calls of the Q80K polymorphism. The results were both highly repeatable and reproducible (>99.7% nucleotide concordance and 100% Q80K concordance). The limits of detection (>2 and ∼5 log10 IU/ml for the Sanger and MiSeq assays, respectively) are sufficiently low to allow genotyping in nearly all chronically infected treatment-naive persons. No systematic bias in the under- or overamplification of minority variants was observed. Coinfection with other viruses (e.g., HIV and hepatitis B virus [HBV]) did not affect the assay results. The two independent HCV NS3 sequencing assays with the automated analysis procedures described here are useful tools to screen for the Q80K polymorphism and other HCV protease inhibitor drug resistance mutations.

Regulation of Nav1.7: A Conserved SCN9A Natural Antisense Transcript Expressed in Dorsal Root Ganglia.

The Nav1.7 voltage-gated sodium channel, encoded by SCN9A, is critical for human pain perception yet the transcriptional and post-transcriptional mechanisms that regulate this gene are still incompletely understood. Here, we describe a novel natural antisense transcript (NAT) for SCN9A that is conserved in humans and mice. The NAT has a similar tissue expression pattern to the sense gene and is alternatively spliced within dorsal root ganglia. The human and mouse NATs exist in cis with the sense gene in a tail-to-tail orientation and both share sequences that are complementary to the terminal exon of SCN9A/Scn9a. Overexpression analyses of the human NAT in human embryonic kidney (HEK293A) and human neuroblastoma (SH-SY5Y) cell lines show that it can function to downregulate Nav1.7 mRNA, protein levels and currents. The NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus, such as Inherited Primary Erythromelalgia, Paroxysmal Extreme Pain Disorder and Painful Small Fibre Neuropathy, but who do not contain mutations in the sense gene. Our results strongly suggest the SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man.

Prenatal diagnosis of critical congenital heart disease reduces risk of death from cardiovascular compromise prior to planned neonatal cardiac surgery: a meta-analysis.

OBJECTIVE: To determine if prenatal diagnosis improves the chance that a newborn with critical congenital heart disease will survive to undergo planned cardiac surgery. METHODS: A systematic review of the medical literature identified eight studies which met the following criteria: compared outcomes between newborns with prenatal and those with postnatal diagnosis of critical congenital heart disease; compared groups of patients with the same anatomical diagnosis; provided detailed information on cardiac anatomy; included detailed information on preoperative cause of death. A meta-analysis was performed to assess differences in preoperative mortality rates between newborns with prenatal diagnosis and those with postnatal diagnosis. Patients with established risk factors for increased mortality (high risk) and those whose families chose comfort care rather than cardiac surgery were excluded. RESULTS: In patients with comparable anatomy, standard risk, a parental desire to treat and optimal care, newborns with a prenatal diagnosis of critical congenital heart disease were significantly less likely to die prior to planned cardiac surgery than were those with a comparable postnatal diagnosis (pooled odds ratio, 0.26; 95% CI, 0.08-0.84). CONCLUSIONS: For newborns most likely to benefit from treatment for their critical congenital heart disease, because they did not have additional risk factors and their families pursued treatment, prenatal diagnosis reduced the risk of death prior to planned cardiac surgery relative to patients with a comparable postnatal diagnosis. Further study and efforts to improve prenatal diagnosis of congenital heart disease should therefore be considered.

Validation of virtual-reality-based simulations for endoscopic sinus surgery.

BACKGROUND: Virtual reality (VR) simulators provide an alternative to real patients for practicing surgical skills but require validation to ensure accuracy. Here, we validate the use of a virtual reality sinus surgery simulator with haptic feedback for training in Otorhinolaryngology - Head & Neck Surgery (OHNS). METHODS: Participants were recruited from final-year medical students, interns, resident medical officers (RMOs), OHNS registrars and consultants. All participants completed an online questionnaire after performing four separate simulation tasks. These were then used to assess face, content and construct validity. anova with post hoc correlation was used for statistical analysis. RESULTS: The following groups were compared: (i) medical students/interns, (ii) RMOs, (iii) registrars and (iv) consultants. Face validity results had a statistically significant (P < 0.05) difference between the consultant group and others, while there was no significant difference between medical student/intern and RMOs. Variability within groups was not significant. Content validity results based on consultant scoring and comments indicated that the simulations need further development in several areas to be effective for registrar-level teaching. However, students, interns and RMOs indicated that the simulations provide a useful tool for learning OHNS-related anatomy and as an introduction to ENT-specific procedures. CONCLUSIONS: The VR simulations have been validated for teaching sinus anatomy and nasendoscopy to medical students, interns and RMOs. However, they require further development before they can be regarded as a valid tool for more advanced surgical training.